Genetic variants useful for risk assessments of coronary artery disease and myocardial infarction

ABSTRACT

The invention relates to methods of risk assessment and diagnosis of susceptibility to coronary artery disease and myocardial infarction, by assessing the presence or absence of alleles of certain polymorphic markers found to be associated with coronary artery disease and myocardial infarction. The invention also relates to methods for use of such polymorphic markers for predicting drug response to drugs for treating cardiovascular disease, or for monitoring the effectiveness of such drugs. The invention further relates to kits encompassing reagents for use in these methods.

BACKGROUND OF THE INVENTION Epidemiology and Etiology

Cardiovascular diseases continue to be the principal cause of death in developed countries (Bonow, R O et al., Circulation 106:1602-05 (2002)). The costs of these diseases are high both in terms of morbidity and mortality, as well as in terms of the financial burden on health care systems. The major complications of coronary artery disease, i.e. Myocardial Infarction (MI) and Acute Coronary Syndrome (ACS), are the leading causes of hospital admissions in industrialized countries. Of all deaths caused by cardiovascular diseases, more than half are attributed to heart attack (myocardial infarction (MI)). The cost of the disease is high both in terms of morbidity and mortality, as well as in terms of the financial burden on the health care systems. According to the NHLBI's ARIC study (Thom, T et al., Circulation 113:e85-151 (2006)), the annual rate of first heart attack (MI or coronary heart disease (CHD) death) per 1000 individuals for ages 65-74 are 19.2 and 6.8, in European American men and women, respectively. For the same age group, the rates are 21.6 and 8.6, in African American men and women respectively. In the older age groups these numbers are much higher with the lifetime risk after the age of 40 of developing heart attack being 49% for men and 32% for women.

Myocardial infarction generally occurs when there is an abrupt decrease in coronary blood flow following a thrombotic occlusion of a coronary artery previously damaged by atherosclerosis (i.e. in subjects with coronary artery disease). In most cases, infarction occurs when an atherosclerotic plaque fissures, ruptures or ulcerates and when conditions favor thrombogenesis. In rare cases, infarction may be due to coronary artery occlusion caused by coronary emboli, congenital abnormalities, coronary spasm, and a wide variety of systemic, particularly inflammatory diseases. Medical risk factors for MI include cigarette smoking, diabetes, hypertension and serum total cholesterol levels >200 mg/dL, elevated serum LDL cholesterol, and low serum HDL cholesterol. Event rates in individuals without a prior history of cardiovascular disease are about 1%. In individuals who have had a first MI or ACS, the risk of a repeat MI within the next year is 10-14%, despite maximal medical management including angioplasty and stent placement.

Atherosclerosis can affect vascular beds in many large and medium arteries. Myocardial infarction and unstable angina (acute coronary syndrome (ACS)) stem from coronary artery atherosclerosis (coronary artery disease), while ischemic stroke most frequently is a consequence of carotid or cerebral artery atherosclerosis. Limb ischemia caused by peripheral arterial occlusive disease (PAOD) may occur as a consequence of iliac, femoral and popliteal artery atherosclerosis. The atherosclerotic diseases remain common despite the wide-spread use of medications that inhibit thrombosis (aspirin) or treat medical risk factors such as elevated cholesterol levels in blood (statins), diabetes, or hypertension (diuretics and antihypertensives).

Atherosclerotic disease is initiated by the accumulation of lipids within the artery wall, and in particular, the accumulation of low-density lipoprotein (LDL) cholesterol. The trapped LDL becomes oxidized and internalized by macrophages. This causes the formation of atherosclerotic lesions containing accumulations of cholesterol-engorged macrophages, referred to as “foam cells”. As disease progresses, smooth muscle cells proliferate and grow into the artery wall forming a “fibrous cap” of extracellular matrix enclosing a lipid-rich, necrotic core. Present in the arterial walls of most people throughout their lifetimes, fibrous atherosclerotic plaques are relatively stable. Such fibrous lesions cause extensive remodeling of the arterial wall, outwardly displacing the external, elastic membrane, without reduction in luminal diameter or serious impact on delivery of oxygen to the heart. Accordingly, patients can develop large, fibrous atherosclerotic lesions without luminal narrowing until late in the disease process. However, the coronary arterial lumen can become gradually narrowed over time and in some cases compromise blood flow to the heart, especially under high demand states such as exercise. This can result in reversible ischemia causing chest pain relieved by rest called stable angina.

In contrast to the relative stability of fibrous atherosclerotic lesions, the culprit lesions associated with myocardial infarction and unstable angina (each of which are part of the acute coronary syndrome) are characterized by a thin fibrous cap, a large lipid core, and infiltration of inflammatory cells such as T-lymphocytes and monocyte/macrophages. Non-invasive imaging techniques have shown that most MI's occur at sites with low- or intermediate-grade stenoses, indicating that coronary artery occlusion is due most frequently to rupture of culprit lesions with consequent formation of a thrombus or blood clot and not solely due to luminal narrowing by stenosis. Plaque rupture may be due to erosion or uneven thinning of the fibrous cap, usually at the margins of the lesion where macrophages enter, accumulate, and become activated by a local inflammatory process. Thinning of the fibrous cap may result from degradation of the extracellular matrix by proteases released from activated macrophages. These changes producing plaque instability and risk of MI may be augmented by production of tissue-factor procoagulant and other factors increasing the likelihood of thrombosis.

In acute coronary syndrome, the culprit lesion showing rupture or erosion with local thrombosis typically is treated by angioplasty or by balloon dilation and placement of a stent to maintain luminal patency. Patients experiencing ACS are at high risk for a second coronary event due to the multi-vessel nature of coronary artery disease with event rates approaching 10-14% within 12 months after the first incident.

The emerging view of MI is as an inflammatory disease of the arterial vessel wall on preexisting chronic atherosclerotic lesions, sometimes triggering rupture of culprit lesions and leading to local thrombosis and subsequent myocardial infarction. The process that triggers and sustains arterial wall inflammation leading to plaque instability is unknown, however, it results in the release into the circulation of tumor necrosis factor alpha and interleukin-6. These and other cytokines or biological mediators released from the damaged vessel wall stimulate an inflammatory response in the liver causing elevation in several non-specific general inflammatory markers including C-reactive protein. Although not specific to atherosclerosis, elevated C-reactive protein (CRP) and serum amyloid A appear to predict risk for MI, perhaps as surrogates for vessel wall inflammation. Many general inflammatory markers predict risk of coronary heart disease, although these markers are not specific to atherosclerosis. For example, Stein (Stein, S., Am J Cardiol, 87 (suppl):21A-26A (2001)) discusses the use of any one of the following serum inflammatory markers as surrogates for predicting risk of coronary heart disease including C-reactive protein (CRP), serum amyloid A, fibrinogen, interleukin-6, tissue necrosis factor-alpha, soluble vascular cell adhesion molecules (sVCAM), soluble intervascular adhesion molecules (sICAM), E-selectin, matrix metalloprotease type-1, matrix metalloprotease type-2, matrix metalloprotease type-3, and matrix metalloprotease type-9. Elevation in one more of these serum inflammatory markers is not specific to coronary heart disease but also occurs with age or in association with cerebrovascular disease, peripheral vascular disease, non-insulin dependent diabetes, osteoarthritis, bacterial infection, and sepsis. Elevated CRP or other serum inflammatory markers is also prognostic for increased risk of a second myocardial infarct in patients with a previous myocardial infarct (Retterstol, L. et al., Atheroscler., 160: 433-440 (2002)).

Although classical risk factors such as smoking, hyperlipidemia, hypertension, and diabetes are associated with many cases of coronary heart disease (CHD) and MI, many patients do not have involvement of these risk factors. In fact, many patients who exhibit one or more of these risk factors do not develop MI. Family history has long been recognized as one of the major risk factors. Although some of the familial clustering of MI reflects the genetic contribution to the other conventional risk factors, a large number of studies have suggested that there are significant genetic susceptibility factors, beyond those of the known risk factors (Friedlander Y, et al., Br. Heart J. 1985; 53:382-7, Shea S. et al., J. Am. Coll. Cardiol. 1984; 4:793-801, and Hopkins P. N., et al., Am. J. Cardiol. 1988; 62:703-7). Major genetic susceptibility factors have only been identified for the rare Mendelian forms of hyperlipidemia such as a familial hypercholesterolemia.

Genetic Risk Factors

Genetic risk of disease is conferred by subtle differences in genes among individuals in a population. Genes differ between individuals most frequently due to single nucleotide polymorphisms (SNP), although other variations are also important. SNPs are located on average every 1000 base pairs in the human genome. Accordingly, a typical human gene containing 250,000 base pairs may contain 250 different SNPs. Only a minor number of SNPs are located in exons and alter the amino acid sequence of the protein encoded by the gene. Most SNPs have no effect on gene function, while others may alter transcription, splicing, translation, or stability of the mRNA encoded by the gene. Additional genetic polymorphisms in the human genome are caused by insertions, deletions, translocations, or inversions of either short or long stretches of DNA. Genetic polymorphisms conferring disease risk may therefore directly alter the amino acid sequence of proteins, may increase the amount of protein produced from the gene, or may decrease the amount of protein produced by the gene.

As genetic polymorphisms conferring risk of disease are uncovered, genetic testing for such risk factors is becoming important for clinical medicine. Examples are apolipoprotein E testing to identify genetic carriers of the ApoE4 polymorphism in dementia patients for the differential diagnosis of Alzheimer's disease, and of Factor V Leiden testing for predisposition to deep venous thrombosis. More importantly, in the treatment of cancer, diagnosis of genetic variants in tumor cells is used for the selection of the most appropriate treatment regime for the individual patient. In breast cancer, genetic variation in estrogen receptor expression or heregulin type 2 (Her2) receptor tyrosine kinase expression determine if anti-estrogenic drugs (tamoxifen) or anti-Her2 antibody (Herceptin) will be incorporated into the treatment plan. In chronic myeloid leukemia (CML) diagnosis of the Philadelphia chromosome genetic translocation fusing the genes encoding the Bcr and Abl receptor tyrosine kinases indicates that Gleevec (STI571), a specific inhibitor of the Bcr-Abl kinase should be used for treatment of the cancer. For CML patients with such a genetic alteration, inhibition of the Bcr-Abl kinase leads to rapid elimination of the tumor cells and remission from leukemia.

The familial clustering of CAD and MI has long been recognized and family history is considered one of the major risk factors for MI. Evidence for a genetic contribution to MI has been provided by both twin and family studies. These studies have estimated the heritability of MI to be 0.26 in males and 0.60 in females (Jorde, L. et al. Medical Genetics 3^(rd) ed. St. Louis: Mosby (2003)) and that the concordance rates for monzygotic vs. dizygotic twins is 0.39 vs. 0.26 for males and 0.44 vs. 0.14 for females. A longitudinal study of 21,004 Swedish twins showed that the relative hazard of death from CAD when one twin died of an early-onset CAD (defined as before age of 55 for males and 65 for females), compared to the hazard ratio when one's twin did not die of early-onset CAD, was 8.1 and 3.8 for male monozygotic and dizygotic twins, respectively (Marenberg, Me., N Engl J Med 330:1041-46 (1994)). The corresponding relative hazard for female twins was 15 for monozygotic twins and 2.6 for dizygotic twins.

Family studies have consistently demonstrated that having a first degree relative with premature CAD death increases the risk of developing CAD (Schildkraut, 3M et al Am J Cardiol 64:555-59 (1989); Slack, 3 & Evans, K A, J Med Genet 3:239-57 (1966)), although the reported increase in risk has varied between studies. The mechanisms/processes by which the family history contributes to MI are currently not well defined. Some of the familial clustering of MI may reflect the familial aggregation to the other conventional risk factors. However, a large number of studies, including the Reykjavik Cohort Study, have suggested that there are significant genetic susceptibility factors, beyond those of the known risk factors (Friedlander, Y., Br Heart J 53:382-87 (1985); Shea, S., J Am Coll Cardiol 4:793-801 (1984); Andresdottir, M B, Eur Heart J 23:1655-63 (2002)). The Reykjavik Cohort Study in Iceland examined the relationship between the history of MI in first-degree relatives and the risk of developing CHD (MI or coronary revascularization) in a large prospective study. Compared with subjects without a family history, the hazard ratio of CHD was 1.75 (95% CI: 1.59-1.92) for men and 1.83 (1.60-2.11) for women, with one or more first-degree relatives with MI, and after adjusting for the conventional risk factors, it was 1.66 (1.51-1.82) and 1.64 (1.43-1.89) for men and women, respectively (Andresdottir, M B, Eur Heart J 23:1655-63 (2002)).

Case-control association studies have suggested the involvement of specific genetic susceptibility variants for MI. The majority of those studies have focused on variants in selected candidate genes (the candidate gene approach), genes that might be involved in the pathogenesis of the disease, or in the development of the intermediate phenotype (e.g. known risk factors). In most cases SNPs that change amino acids or are in promoter regions of genes, have been tested for association. Two studies have tested variants within multiple candidate genes for association with MI. In one, association of C1019T polymorphism in the connexin 37 gene to MI in men and 4G-668-5G polymorphism in the plasminogen-activator-inhibitor type 1 gene and the 5A-1171/6A polymorphism in the stromelysin-1 gene in women Was reported (Yamada, Y. et al N Engl J Med 347:1916-23 (2002)). Another study examining 72 SNPs in 62 candidate genes in individuals with premature MI and controls from the US, showed that three variants in genes encoding thrombosponding-4, thrombospondin-2, and thrombospondin-1, associated with premature MI (Topol, E J, et al Circulation 104:2641-44 (2001). A more recent study tested 11,053 SNPs in 6,891 genes for association to MI in a group of European-Americans (Shiffman, d., et al Am J Hum Genet 77:596-605 (2005)). The SNPs tested were primarily selected as variants likely to affect protein function or expression. MI associated variants in four novel genes (KIAA0992, ROS1, TAS2R50, and OR13G1) were identified through this effort. Importantly, variants identified as associated to MI in the above studies remain to be validated in replication studies. Their involvement in the etiology of MI therefore remains uncertain.

Recently, genetic susceptibility variants for CAD and MI were identified on chromosome 9, within a region that contains the CDKN2A and CDKN2B genes (Helgadottir, A. et al, Science 316:1491-93 (2007); McPherson, R. et al, Science 316:1488-91 (2007); The Wellcome Trust Case Control Consortium, Nature 447:661-78 (2007); Samani, N J et al, N Engl J Med 357:443-53 (2007)). Follow-up investigations have shown that the variants, which are all located within a region of high linkage disequilibrium (LD), also contribute to risk of intracranial aneurysm and abdominal aortic aneurysm (Helgadottir, A. et al, Nature Genet 40:217-24 (2008)), showing that these variants not only contribute to MI and CAD, but also to cardiovascular disease in general.

Cardiovascular disease remains the most important cause or morbidity and mortality and there is a large unmet medical need for its prevention. Identifying the key pathways involved in MI and CAD may facilitate development of new therapeutics and diagnostics. Identification of genetic risk factors for MI and CAD may offer clinical practitioners valuable diagnostic and prognostic tools. Genetic variants that are found to be an important key to the presentation of clinical symptoms in MI may also facilitate drug development, through the identification of novel drug targets.

There is thus an unmet need for identification of additional genetic variants that confer susceptibility of CAD and MI. The present invention provides such variants.

SUMMARY OF THE INVENTION

The present invention relates to methods of risk assessment, diagnosis and/or prognosis of coronary artery disease (CAD) and myocardial infarction (MI). Certain genetic variants have been found to be associated with risk of CAD and/or MI. The invention thus relates to methods of assessing increased susceptibility to CAD and/or MI, as well as methods of assessing a decreased susceptibility to CAD and/or MI, or determine a protection against CAD and/or MI. The methods of the invention relate to the evaluation of certain polymorphic markers, as described herein, that have been found to be useful in disease prediction and management, through their association with susceptibility of coronary artery disease and myocardial infarction.

In one aspect, the invention relates to a method for determining a susceptibility to coronary artery disease or myocardial infarction in a human individual, comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual or in a genotype dataset derived from the individual, wherein the at least one polymorphic marker is selected from the polymorphic markers set forth in Table 4, and markers in linkage disequilibrium therewith, and wherein the presence of the at least one allele is indicative of a susceptibility to coronary artery disease or myocardial infarction. The method may in one embodiment relate to determination of the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual. In another embodiment, the method relates to determination of the presence or absence of at least one allele of at least one polymorphic marker in a genotype dataset derived from the individual. The genotype dataset can be derived from the individual in the sense that the information that it contains (genotype information) relates to a particular nucleic acid sample as a template from a single individual, for whom genetic information is derived.

In another aspect, the present invention relates to a method of determining a susceptibility to coronary artery disease or myocardial infarction in a human individual, comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual, wherein the at least one polymorphic marker is selected from rs11751605 (SEQ ID NO:1), and markers in linkage disequilibrium therewith, wherein determination of the presence or absence of the at least one allele is indicative of a susceptibility to coronary artery disease or myocardial infarction. In one embodiment, the at least one polymorphic marker is selected from the markers set forth in Table 5, and markers in linkage disequilibrium therewith.

In an alternative aspect, the invention relates to a method of diagnosing a susceptibility to coronary artery disease or myocardial infarction in a human individual, the method comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual, or in a genotype dataset derived from the individual, wherein the at least one polymorphic marker is selected from rs11751605 (SEQ ID NO:1), and markers in linkage disequilibrium therewith, wherein the presence of the at least one allele is indicative of a susceptibility to coronary artery disease or myocardial infarction.

In another aspect, the invention relates to a method of determining a susceptibility to coronary artery disease or myocardial infarction in a human individual, comprising determining whether at least one at-risk allele in at least one polymorphic marker is present in a genotype dataset derived from the individual, wherein the at least one polymorphic marker is selected from the markers set forth in Table 4, and markers in linkage disequilibrium therewith, and wherein determination of the presence of the at least one at-risk allele is indicative of increased susceptibility to coronary artery disease or myocardial infarction in the individual.

The genotype dataset comprises in one embodiment information about marker identity, and the allelic status of the individual, i.e. information about the identity of the two alleles carried by the individual for the marker. The genotype dataset may comprise allelic information about one or more marker, including two or more markers, three or more markers, five or more markers, one hundred or more markers, etc. In some embodiments, the genotype dataset comprises genotype information from a whole-genome assessment of the individual including hundreds of thousands of markers, or even one million or more markers.

In certain embodiments, the at least one polymorphic marker is selected from the markers set forth in Table 4. In certain other embodiments, the at least one polymorphic marker is associated with the Lipoprotein (a) gene. In certain other embodiments, the at least one polymorphic marker is selected from rs11751605, rs6076623, rs1412444, rs2163612, rs1029396, rs2243547, rs12534186, rs12134779, rs7158073, rs254850, rs2417821, rs7661204, rs4921437, rs832540, rs324594, rs1741318, rs9902941, rs7709212, rs2946534, rs6556861, rs8050136, rs3751812, rs4769613, rs2243548, rs12459084, rs2074464, rs2244871, rs270654, rs854787, rs7944761, rs4779984, rs6502622, rs3183702, rs1433048, rs4925119, rs2476601, rs870347, rs334198, rs854813, rs7753765, rs4925114, rs270661, rs953861, rs10045431, rs8003722, rs2297538, rs12329252, rs3748744, rs4704400, rs3102526, rs2110209, rs1870843 and rs3134517.

In one embodiment, the method of determining a susceptibility, or diagnosing a susceptibility of, coronary artery disease or myocardial infarction, further comprises assessing the frequency of at least one haplotype in the individual. In one such embodiment, the at least one haplotype is selected from haplotypes that are in linkage disequilibrium with at least one marker as set forth in Table 4. In another embodiment, the at least one haplotype is selected from the haplotypes that are in linkage disequilibrium with rs11751605 (SEQ ID NO:1).

In certain embodiments of the invention, determination of the presence of at least one at-risk allele of at least one polymorphic Marker in a nucleic acid sample from the individual is indicative of an increased susceptibility to coronary artery disease or myocardial infarction. In one embodiment, the increased susceptibility is characterized by a relative risk (RR) or odds ratio (OR) of at least 1.15. In another embodiment, the increased susceptibility is characterized by a relative risk (RR) or odds ratio (OR) of at least 1.20.

In some embodiments, the presence of allele C in rs11751605, allele T in rs6076623, allele A in rs1412444, allele G in rs2163612 or allele G in rs1029396 is indicative of increased susceptibility of coronary artery disease or myocardial infarction in the individual.

In some other embodiments, the presence of at least one protective allele in a nucleic acid sample from the individual is indicative of a decreased susceptibility of coronary artery disease or myocardial infarction. In another embodiment, the absence of at least one at-risk allele in a nucleic acid sample from the individual is indicative of a decreased susceptibility of coronary artery disease or myocardial infarction.

Another aspect of the invention relates to a method of assessing a susceptibility to coronary artery disease or myocardial infarction in a human individual, comprising screening a nucleic acid from the individual for at least one polymorphic marker or haplotype in the genomic segment with the sequence as set forth in any one of SEQ ID NO:1-172 that correlates with increased occurrence of coronary artery disease or myocardial infarction in a human population, wherein the presence of an at-risk marker allele in the at least one polymorphism or an at-risk haplotype in the nucleic acid identifies the individual as having elevated susceptibility to coronary artery disease or myocardial infarction, and wherein the absence of the at least one at-risk marker allele or at-risk haplotype in the nucleic acid identifies the individual as not having the elevated susceptibility.

In one such embodiment, the at least one polymorphic marker or haplotype comprises at least one polymorphic marker selected from the markers set forth in Table 4, and polymorphic markers in linkage disequilibrium therewith.

Certain embodiments of the invention further comprise a step of screening the nucleic acid for the presence of at least one at-risk genetic variant for a coronary artery disease or myocardial infarction not associated with, i.e. not in linkage disequilibrium with, any one of the markers set forth in Table 4. Such additional genetic variants can in specific embodiments include any variant that has been identified as a susceptibility or risk variant for coronary artery disease or myocardial infarction.

In another aspect of the present invention, the presence of the marker or haplotype found to be associated with coronary artery disease or myocardial infarction, and as such useful for determining a susceptibility to coronary artery disease or myocardial infarction, is indicative of a different response rate of the subject to a particular treatment modality for coronary artery disease or myocardial infarction.

In another aspect, the invention relates to a method of identification of a marker for use in assessing susceptibility to coronary artery disease or myocardial infarction in human individuals, the method comprising:

-   -   identifying at least one polymorphic marker in linkage         disequilibrium with at least one of the markers set forth in         Table 4;     -   determining the genotype status of a sample of individuals         diagnosed with, or having a susceptibility to, coronary artery         disease or myocardial infarction; and     -   determining the genotype status of a sample of control         individuals;         wherein a significant difference in frequency of at least one         allele in at least one polymorphism in individuals diagnosed         with, or having a susceptibility to, coronary artery disease or         myocardial infarction, as compared with the frequency of the at         least one allele in the control sample is indicative of the at         least one polymorphism being useful for assessing susceptibility         to coronary artery disease or myocardial infarction.

In one embodiment, “significant” is determined by statistical means, e.g. the difference is statistically significant. In one such embodiment, statistical significance is characterized by a P-value of less than 0.05. In other embodiments, the statistical significance is characterized a P-value of less than 0.01, less than 0.001, less than 0.0001, less than 0.00001, less than 0.000001, less than 0.0000001, less than 0.0000000001, or less than 0.00000001.

In one embodiment, an increase in frequency of the at least one allele in the at least one polymorphism in individuals diagnosed with, or having a susceptibility to, coronary artery disease or myocardial infarction, as compared with the frequency of the at least one allele in the control sample, is indicative of the at least one polymorphism being useful for assessing increased susceptibility to coronary artery disease or myocardial infarction. In another embodiment, a decrease in frequency of the at least one allele in the at least one polymorphism in individuals diagnosed with, or having a susceptibility to, a coronary artery disease or myocardial infarction, as compared with the frequency of the at least one allele in the control sample is indicative of the at least one polymorphism being useful for assessing decreased susceptibility to, or protection against, the coronary artery disease or myocardial infarction.

Another aspect of the invention relates to a method of genotyping a nucleic acid sample obtained from a human individual, comprising determining the presence or absence of at least one allele of at least one polymorphic marker in the sample, wherein the at least one marker is selected from the markers set forth in Table 4, and markers in linkage disequilibrium therewith, and wherein determination of the presence or absence of the at least one allele of the at least one polymorphic marker is predictive of a susceptibility of coronary artery disease or myocardial infarction.

In one embodiment, genotyping comprises amplifying a segment of a nucleic acid that comprises the at least one polymorphic marker by Polymerase Chain Reaction (PCR), using a nucleotide primer pair flanking the at least one polymorphic marker. In another embodiment, genotyping is performed using a process selected from allele-specific probe hybridization, allele-specific primer extension, allele-specific amplification, nucleic acid sequencing, 5′-exonuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, and single-stranded conformation analysis. In one particular embodiment, the process comprises allele-specific probe hybridization. In another embodiment, the process comprises DNA sequencing. In a preferred embodiment, the method comprises:

-   -   1) contacting copies of the nucleic acid with a detection         oligonucleotide probe and an enhancer oligonucleotide probe         under conditions for specific hybridization of the         oligonucleotide probe with the nucleic acid;         -   wherein         -   a) the detection oligonucleotide probe is from 5-100             nucleotides in length and specifically hybridizes to a first             segment of the nucleic add whose nucleotide sequence is             given by any one of SEQ ID NO:1-172 that comprises at least             one polymorphic site;         -   b) the detection oligonucleotide probe comprises a             detectable label at its 3′ terminus and a quenching moiety             at its 5′ terminus;         -   c) the enhancer oligonucleotide is from 5-100 nucleotides in             length and is complementary to a second segment of the             nucleotide sequence that is 5′ relative to the             oligonucleotide probe, such that the enhancer             oligonucleotide is located 3′ relative to the detection             oligonucleotide probe when both oligonucleotides are             hybridized to the nucleic acid; and         -   d) a single base gap exists between the first segment and             the second segment, such that when the oligonucleotide probe             and the enhancer oligonucleotide probe are both hybridized             to the nucleic acid, a single base gap exists between the             oligonucleotides;     -   2) treating the nucleic acid with an endonuclease that will         cleave the detectable label from the 3′ terminus of the         detection probe to release free detectable label when the         detection probe is hybridized to the nucleic acid; and     -   3) measuring free detectable label, wherein the presence of the         free detectable label indicates that the detection probe         specifically hybridizes to the first segment of the nucleic         acid, and indicates the sequence of the polymorphic site as the         complement of the detection probe.

In a particular embodiment, the copies of the nucleic acid are provided by amplification by Polymerase Chain Reaction (PCR). In another embodiment, the susceptibility determined is increased susceptibility. In another embodiment, the susceptibility determined is decreased susceptibility.

Another aspect of the invention relates to a method of assessing an individual for probability of response to a therapeutic agent for preventing and/or ameliorating symptoms associated with coronary artery disease or myocardial infarction, comprising: determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual, wherein the at least one polymorphic marker is selected from the markers set forth in Table 4, and markers in linkage disequilibrium therewith, wherein determination of the presence of the at least one allele of the at least one marker is indicative of a probability of a positive response to coronary artery disease or myocardial infarction therapeutic agent. In one embodiment, the at least one polymorphic marker is selected from marker rs11751605, rs6076623, rs1412444, rs2163612 and rs1029396, and markers in linkage disequilibrium therewith. In one embodiment, the therapeutic agent is selected from beta blockers, anticoagulation agents, including heparin and/or low molecular weigh heparin, antiplatelet agents, such as clopidogrel, aspirin, beta blockers, including metoprolol and carvedilol, ACE inhibitors, Statins, Aldosterone antagonists, including eplerenone, leukotriene synthesis inhibitors, the agents set forth in Agent Table I, Agent Table II, (R)-(+)-alpha-cyclopentyl-4-(2-quinolinylmethoxy)-Benzeneacetic acid, atreleuton, and 4-{(S)-2-[4-(4-Chloro-phenoxy)-phenoxymethyl]-pyrrolidin-1-yl}-butyramide, also known as DG-051. Other embodiments may include any one or a combination of the therapeutic agents described herein to be useful for therapeutic intervention of coronary artery disease or myocardial infarction.

Yet another aspect of the invention relates to a method of predicting prognosis of an individual diagnosed with coronary artery disease or myocardial infarction, the method comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual, wherein the at least one polymorphic marker is selected from the group consisting of the markers set forth in Table 3, and markers in linkage disequilibrium therewith, wherein determination of the presence of the at least one allele is indicative of a worse prognosis of coronary artery disease or myocardial infarction in the individual. The prognosis may in certain embodiment relate to susceptibility of recurrent MI events, recurrent stroke events, or susceptibility to other complications relating to coronary artery disease or myocardial infarction.

A further aspect of the invention relates to a method of monitoring progress of a treatment of an individual undergoing treatment for coronary artery disease or myocardial infarction, the method comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual, wherein the at least one polymorphic marker is selected from the group consisting of the markers set forth in Table 3, and markers in linkage disequilibrium therewith, wherein determination of the presence of the at least one allele is indicative of the treatment outcome of the individual. The treatment may in certain embodiments be surgical treatment. In other embodiments, the treatment is by administration of a therapeutic agent, optionally including lifestyle changes or alterations in environmental exposure to risk factors for coronary artery disease or myocardial infarction, as described further herein.

In one embodiment, the method further comprises assessing at least one biomarker in a sample from the individual. The biomarker is in certain embodiments a cardiac marker or an inflammatory marker. In one embodiment, the at least one biomarker is selected from creatin kinase, troponin, glycogen phosphorylase, C-reactive protein (CRP), serum amyloid A, fibrinogen, interleukin-6, tissue necrosis factor-alpha, soluble vascular cell adhesion molecules (sVCAM), soluble intervascular adhesion molecules (sICAM), E-selectin, matrix metalloprotease type-1, matrix metalloprotease type-2, matrix metalloprotease type-3, matrix metalloprotease type-9, serum sCD40L, leukotrienes, leukotriene metabolites, interleukin-6, tissue necrosis factor-alpha, myeloperoxidase (MPO), and N-tyrosine. In one embodiment, the leukotriene is selected from LTB4, LTC4, LTD4 and LTE4. In another embodiment, the method further comprises analyzing non-genetic information to make risk assessment, diagnosis, or prognosis of the individual. The non-genetic information is in one embodiment selected from age, gender, ethnicity, socioeconomic status, previous disease diagnosis, medical history of subject, family history of coronary artery disease or myocardial infarction, biochemical measurements, and clinical measurements. In a particular preferred embodiment, a further step comprising calculating overall risk is employed.

Another aspect of the invention relates to analyzing a sample comprising genomic DNA from a human individual or a genotype dataset derived from a human individual for the presence or absence of at least one at-risk allele of at least one at-risk variant for coronary artery disease or myocardial infarction not in linkage disequilibrium with any one of the markers set forth in Table 4. Thus, the variants described herein to be associated with coronary artery disease or myocardial infarction may be combined with other genetic variants for coronary artery disease or myocardial infarction, that are not genetically related (i.e., not in linkage disequilibrium with) the markers described herein. Such analysis may be undertaken in combination with any of the methods described herein. Furthermore any two markers herein, or any other combination of markers and/or haplotypes described herein to be associated with coronary artery disease or myocardial infarction may be combined to assess an increased susceptibility to coronary artery disease or myocardial infarction.

In some embodiments of the methods of the invention, non-genetic information is analyzed, to make risk assessment, diagnosis, or prognosis of the individual. The non-genetic information is in certain embodiments selected from age, gender, ethnicity, socioeconomic status, previous disease diagnosis, medical history of subject, family history of coronary artery disease or myocardial infarction, biochemical measurements, and clinical measurements. Combined genetic factors and/or combinations of genetic and non-genetic factors may be analyzed by known methods, to generate a combined risk.

The invention also relates to a kit for assessing susceptibility to a coronary artery disease or myocardial infarction in a human individual, the kit comprising reagents for selectively detecting the presence or absence of at least one allele of at least one polymorphic marker in the genome of the individual, wherein the polymorphic marker is selected from the markers set forth in Table 3, and markers in linkage disequilibrium therewith, and wherein the presence of the at least one allele is indicative of a susceptibility to a coronary artery disease or myocardial infarctions.

In one embodiment, the reagents comprise at least one contiguous oligonucleotide that hybridizes to a fragment of the genome of the individual comprising the at least one polymorphic marker, a buffer and a detectable label. In one embodiment, the reagents comprise at least one pair of oligonucleotides that hybridize to opposite strands of a genomic nucleic acid segment obtained from the subject, wherein each oligonucleotide primer pair is designed to selectively amplify a fragment of the genome of the individual that includes one polymorphic marker, and wherein the fragment is at least 30 base pairs in size. In a particular embodiment the at least one oligonucleotide is completely complementary to the genome of the individual. In another embodiment, the at least one oligonucleotide can comprise at least one mismatch to the genome of the individual. In one embodiment, the oligonucleotide is about 18 to about 50 nucleotides in length. In another embodiment, the oligonucleotide is 20-30 nucleotides in length.

In one preferred embodiment, the kit comprises:

a detection oligonucleotide probe that is from 5-100 nucleotides in length; an enhancer oligonucleotide probe that is from 5-100 nucleotides in length; and an endonuclease enzyme; wherein the detection oligonucleotide probe specifically hybridizes to a first segment of the nucleic acid whose nucleotide sequence is given by any one of SEQ ID NO:1-172 that comprises at least one polymorphic site; and wherein the detection oligonucleotide probe comprises a detectable label at its 3′ terminus and a quenching moiety at its 5′ terminus; wherein the enhancer oligonucleotide is from 5-100 nucleotides in length and is complementary to a second segment of the nucleotide sequence that is 5′ relative to the oligonucleotide probe, such that the enhancer oligonucleotide is located 3′ relative to the detection oligonucleotide probe when both oligonucleotides are hybridized to the nucleic acid; wherein a single base gap exists between the first segment and the second segment, such that when the oligonucleotide probe and the enhancer oligonucleotide probe are both hybridized to the nucleic acid, a single base gap exists between the oligonucleotides; and wherein treating the nucleic acid with the endonuclease will cleave the detectable label from the 3′ terminus of the detection probe to release free detectable label when the detection probe is hybridized to the nucleic acid.

A further aspect of the invention relates to the use of an oligonucleotide probe in the manufacture of a diagnostic reagent for diagnosing and/or assessing susceptibility to coronary artery disease or myocardial infarction in a human individual, wherein the probe hybridizes to a segment of a nucleic acid whose nucleotide sequence is given by any one of SEQ ID NO:1-172 that comprises at least one polymorphic site, wherein the fragment is 15-500 nucleotides in length. In one embodiment, the polymorphic site is selected from the polymorphic markers rs11751605, rs6076623, rs1412444, rs2163612 and rs1029396, and markers in linkage disequilibrium therewith

Yet another aspect of the invention relates to a computer-readable medium on which is stored: an identifier for at least one polymorphic marker; an indicator of the frequency of at least one allele of said at least one polymorphic marker in a plurality of individuals diagnosed with a coronary artery disease or myocardial infarction; and an indicator of the frequency of the least one allele of said at least one polymorphic markers in a plurality of reference individuals; wherein the at least one polymorphic marker is selected from the polymorphic markers set forth in Table 4, and markers in linkage disequilibrium therewith. In one embodiment, the at least one polymorphic marker is selected from rs11751605, rs6076623, rs1412444, rs2163612, rs1029396, and markers in linkage disequilibrium therewith.

Another aspect relates to an apparatus for determining a genetic indicator for coronary artery disease or myocardial infarction in a human individual, comprising: a computer readable memory; and a routine stored on the computer readable memory; wherein the routine is adapted to be executed on a processor to analyze marker and/or haplotype information for at least one human individual with respect to at least one polymorphic marker selected from the markers set forth in Table 4, and markers in linkage disequilibrium therewith, and generate an output based on the marker or haplotype information, wherein the output comprises a risk measure of the at least one marker or haplotype as a genetic indicator of coronary artery disease or myocardial infarction for the human individual.

In one embodiment, the routine further comprises an indicator of the frequency of at least one allele of at least one polymorphic marker or at least one haplotype in a plurality of individuals diagnosed with coronary artery disease or myocardial infarction, and an indicator of the frequency of at the least one allele of at least one polymorphic marker or at least one haplotype in a plurality of reference individuals, and wherein a risk measure is based on a comparison of the at least one marker and/or haplotype status for the human individual to the indicator of the frequency of the at least one marker and/or haplotype information for the plurality of individuals diagnosed with coronary artery disease or myocardial infarction.

The present invention, as described herein, may be reduced to practice using any one, or a combination of, the polymorphic markers described herein as being useful for the determination of a susceptibility to coronary artery disease or myocardial infarction. This includes markers that are shown herein to be associated with coronary artery disease or myocardial infarction, but also includes markers that are in linkage disequilibrium with such variants. In one embodiment, the at least one marker is selected from the markers set forth in Table 3. In another embodiment, the at least one marker is selected from the markers set forth in Table 4. In another embodiment, the at least one marker is selected from rs11751605 (SEQ ID NO:1), rs6076623 (SEQ ID NO:2), rs1412444 (SEQ ID NO:3), rs2163612 (SEQ ID NO:4), rs1029396 (SEQ ID NO:5), rs2243547 (SEQ ID NO:6), rs12534186 (SEQ ID NO:7), rs12134779 (SEQ ID NO:8), rs7158073 (SEQ ID NO:9), rs254850 (SEQ ID NO:10), rs2417821 (SEQ ID NO:11), rs7661204 (SEQ ID NO:12), rs4921437 (SEQ ID NO:13), rs832540 (SEQ ID NO:14), rs324594 (SEQ ID NO:15), rs1741318 (SEQ ID NO:16), rs9902941 (SEQ ID NO:17), rs7709212 (SEQ ID NO:18), rs2946534 (SEQ ID NO:19), rs6556861 (SEQ ID NO:20), rs8050136 (SEQ ID NO:21), rs3751812 (SEQ ID NO:22), rs4769613 (SEQ ID NO:23), rs2243548 (SEQ ID NO:24), rs12459084 (SEQ ID NO:25), rs2074464 (SEQ ID NO:26), rs2244871 (SEQ ID NO:27), rs270654 (SEQ ID NO:28), rs854787 (SEQ ID NO:29), rs7944761 (SEQ ID NO:30), rs4779984 (SEQ ID NO:31), rs6502622 (SEQ ID NO:32), rs3183702 (SEQ ID NO:33), rs1433048 (SEQ ID NO:34), rs4925119 (SEQ ID NO:35), rs2476601 (SEQ ID NO:36), rs870347 (SEQ ID NO:37), rs334198 (SEQ ID NO:38), rs854813 (SEQ ID NO:39), rs7753765 (SEQ ID NO:40), rs4925114 (SEQ ID NO:41), rs270661 (SEQ ID NO:42), rs953861 (SEQ ID NO:43), rs10045431 (SEQ ID NO:44), rs8003722 (SEQ ID NO:45), rs2297538 (SEQ ID NO:46), rs12329252 (SEQ ID NO:47), rs3748744 (SEQ ID NO:48), rs4704400 (SEQ ID NO:49), rs3102526 (SEQ ID NO:50), rs2110209 (SEQ ID NO:51), rs1870843 (SEQ ID NO:52) and rs3134517 (SEQ ID NO:53). In another embodiment, the at least one marker is selected from rs11751605 (SEQ ID NO:1), rs6076623 (SEQ ID NO:2), rs1412444 (SEQ ID NO:3), rs2163612 (SEQ ID NO:4), rs1029396 (SEQ ID NO:5). In another embodiment, the at least one marker is selected from rs11751605 (SEQ ID NO:1), rs6076623 (SEQ ID NO:2), rs1412444 (SEQ ID NO:3), rs2163612 (SEQ ID NO:4), rs1029396 (SEQ ID NO:5), rs2243547 (SEQ ID NO:6), rs12534186 (SEQ ID NO:7), rs12134779 (SEQ ID NO:8), rs7158073 (SEQ ID NO:9). In another embodiment, the at least one marker is rs11751605 (SEQ ID NO:1). In another embodiment, the at least one marker is rs6076623 (SEQ ID NO:2). In another embodiment, the at least one marker is rs1412444 (SEQ ID NO:3). In another embodiment, the at least one marker is rs2163612 (SEQ ID NO:4). In another embodiment, the at least one marker is rs1029396 (SEQ ID NO:5). In these embodiments, the at least one marker may optionally be selected from markers in linkage disequilibrium with the at least one marker.

The present invention relates to methods, uses, apparatus or kits useful for detecting or determining a susceptibility to myocardial infarction or coronary artery disease. It is however contemplated that the variants described herein to be correlated with risk of developing myocardial infarction or coronary artery disease may also be risk variants for other cardiovascular diseases. This includes Stroke, Peripheral Artery Disease, Restenosis, Intracranial Aneurysm and Aorta Abdominal Aneurysm. The Restenosis phenotype may for example be Coronary In-stent Restenosis. The In-stent Restenosis may further be either Restenosis following Bare Metal Stent (BMS) placement, or Restenosis following placement of a Drug Eluting Stent (DES).

Variants (markers and/or haplotypes comprising polymorphic markers) in linkage disequilibrium with the markers and haplotypes of the present invention are also useful for the methods and kits of the invention. The invention therefore also pertains to markers in linkage disequilibrium with the markers and haplotypes of the invention. In certain embodiments of the methods, uses, apparatus or kits of the invention, linkage disequilibrium is characterized by specific cutoff values for a quantitative measure of linkage disequilibrium. In one such embodiment, linkage disequilibrium is characterized by specific numerical values, or ranges of numerical values, for r². In another such embodiment, linkage disequilibrium is characterized by specific numerical values, or ranges of numerical values, for |D′|. In yet another embodiment, linkage disequilibrium is characterized by specific numerical values for r² and |D′|, or ranges thereof. In one preferred embodiment, linkage disequilibrium is characterized by values for r² of greater than 0.1. In another preferred embodiment, linkage disequilibrium is characterized by values for r² of greater than 0.2. Other cutoff values for r² are also possible, including, but not limited to, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 0.95, 0.96, 0.97, 0.98, 0.99. In another preferred embodiment, linkage disequilibrium is characterized by values for |D′| of greater than 0.5. In another preferred embodiment, linkage disequilibrium is characterized by values for |D′| of greater than 0.8. Other cutoff values for |D′| are also possible, including, but not limited to, 0.2, 0.3, 0.4, 0.6, 0.7, 0.8, 0.9, 0.95, 0.96, 0.97, 0.98 and 0.99. In certain embodiments, linkage disequilibrium is characterized by numeric cutoff values for either |D′| and r². In one such embodiment linkage disequilibrium is characterized by numerical values for either |D′| of greater than 0.8 and r² of greater than 0.2, or both.

In certain other embodiments of the methods, uses, apparatus or kits of the invention, the individual is of a specific human ancestry. In one embodiment, the ancestry is selected from black African ancestry, Caucasian ancestry and Chinese ancestry. In another embodiment, the ancestry is black African ancestry. In another embodiment, the ancestry is African American ancestry. In another embodiment, the ancestry is European ancestry. In another embodiment, the ancestry is Caucasian ancestry. The ancestry is in certain embodiment self-reported by the individual who undergoes genetic analysis or genotyping. In other embodiments, the ancestry is determined by genetic determination comprising detecting at least one allele of at least one polymorphic marker in a nucleic acid sample from the individual, wherein the presence or absence of the allele is indicative of the ancestry of the individual.

In other particular other embodiments of the methods, uses, apparatus or kits of the invention, the presence of at least one at-risk variant, i.e. an at-risk allele in at least one polymorphic marker or an at-risk haplotype, is indicative of an early onset of coronary artery disease or myocardial infarction. Early onset is in some embodiments categorized as onset before age 75. In other embodiments, early onset is categorized as onset before age 70, before age 65, before age 60, before age 55, before age 50, before age 45, or before age 40. Other values for categorization of age at onset are also contemplated, including, but not limited to, all integer values of age, and such age categories are also within scope of the invention. In certain embodiments, the age at onset is below 50 for males and/or below 60 for females.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise indicated, nucleic acid sequences are written left to right in a 5′ to 3′ orientation. Numeric ranges recited within the specification are inclusive of the numbers defining the range and include each integer or any non-integer fraction within the defined range. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by the ordinary person skilled in the art to which the invention pertains.

The following terms shall, in the present context, have the meaning as indicated:

A “polymorphic marker”, sometime referred to as a “marker”, as described herein, refers to a genomic polymorphic site. Each polymorphic marker has at least two sequence variations characteristic of particular alleles at the polymorphic site. Thus, genetic association to a polymorphic marker implies that there is association to at least one specific allele of that particular polymorphic marker. The marker can comprise any allele of any variant type found in the genome, including SNPs, microsatellites, insertions, deletions, duplications and translocations.

An “allele” refers to the nucleotide sequence of a given locus (position) on a chromosome. A polymorphic marker allele thus refers to the composition (i.e., sequence) of the marker on a chromosome. Genomic DNA from an individual contains two alleles (e.g., allele-specific sequences) for any given polymorphic marker, representative of each copy of the marker on each chromosome. Sequence codes for nucleotides used herein are: A=1, C=2, G=3, T=4. For microsatellite alleles, the CEPH sample (Centre d′Etudes du Polymorphisme Humain, genomics repository, CEPH sample 1347-02) is used as a reference, the shorter allele of each microsatellite in this sample is set as 0 and all other alleles in other samples are numbered in relation to this reference. Thus, e.g., allele 1 is 1 by longer than the shorter allele in the CEPH sample, allele 2 is 2 by longer than the shorter allele in the CEPH sample, allele 3 is 3 by longer than the lower allele in the CEPH sample, etc., and allele −1 is 1 by shorter than the shorter allele in the CEPH sample, allele −2 is 2 by shorter than the shorter allele in the CEPH sample, etc.

Sequence conucleotide ambiguity as described herein is as proposed by IUPAC-IUB. These codes are compatible with the codes used by the EMBL, GenBank, and PIR databases.

IUB code Meaning A Adenosine C Cytidine G Guanine T Thymidine R G or A Y T or C K G or T M A or C S G or C W A or T B C G or T D A G or T H A C or T V A C or G N A C G or T (Any base)

A nucleotide position at which more than one sequence is possible in a population (either a natural population or a synthetic population, e.g., a library of synthetic molecules) is referred to herein as a “polymorphic site”.

A “Single Nucleotide Polymorphism” or “SNP” is a DNA sequence variation occurring when a single nucleotide at a specific location in the genome differs between members of a species or between paired chromosomes in an individual. Most SNP polymorphisms have two alleles. Each individual is in this instance either homozygous for one allele of the polymorphism (i.e. both chromosomal copies of the individual have the same nucleotide at the SNP location), or the individual is heterozygous (i.e. the two sister chromosomes of the individual contain different nucleotides). The SNP nomenclature as reported herein refers to the official Reference SNP (rs) ID identification tag as assigned to each unique SNP by the National Center for Biotechnological Information (NCBI).

A “variant”, as described herein, refers to a segment of DNA that differs from the reference DNA. A “marker” or a “polymorphic marker”, as defined herein, is a variant. Alleles that differ from the reference are referred to as “variant” alleles.

A “microsatellite” is a polymorphic marker that has multiple small repeats of bases that are 2-8 nucleotides in length (such as CA repeats) at a particular site, in which the number of repeat lengths varies in the general population. An “indel” is a common form of polymorphism comprising a small insertion or deletion that is typically only a few nucleotides long.

A “haplotype,” as described herein, refers to a segment of genomic DNA that is characterized by a specific combination of alleles arranged along the segment. For diploid organisms such as humans, a haplotype comprises one member of the pair of alleles for each polymorphic marker or locus. In a certain embodiment, the haplotype can comprise two or more alleles, three or more alleles, four or more alleles, or five or more alleles.

The term “susceptibility”, as described herein, refers to the proneness of an individual towards the development of a certain state (e.g., a certain trait, phenotype or disease), or towards being less able to resist a particular state than the average individual. The term encompasses both increased susceptibility and decreased susceptibility. Thus, particular polymorphic markers and/or haplotypes of the invention may be characteristic of increased susceptibility (i.e., increased risk) of coronary artery disease and myocardial infarction, as characterized by a relative risk (RR) or odds ratio (OR) of greater than one for the particular allele or haplotype. Alternatively, the markers and/or haplotypes of the invention are characteristic of decreased susceptibility (i.e., decreased risk) of coronary artery disease and myocardial infarction, as characterized by a relative risk of less than one.

The term “and/or” shall in the present context be understood to indicate that either or both of the items connected by it are involved. In other words, the term herein shall be taken to mean “one or the other or both”.

The term “look-up table”, as described herein, is a table that correlates one form of data to another form, or one or more forms of data to a predicted outcome to which the data is relevant, such as phenotype or trait. For example, a look-up table can comprise a correlation between allelic data for at least one polymorphic marker and a particular trait or phenotype, such as a particular disease diagnosis, that an individual who comprises the particular allelic data is likely to display, or is more likely to display than individuals who do not comprise the particular allelic data. Look-up tables can be multidimensional, i.e. they can contain information about multiple alleles for single markers simultaneously, or the can contain information about multiple markers, and they may also comprise other factors, such as particulars about diseases diagnoses, racial information, biomarkers, biochemical measurements, therapeutic methods or drugs, etc.

A “computer-readable medium”, is an information storage medium that can be accessed by a computer using a commercially available or custom-made interface. Exemplary compute-readable media include memory (e.g., RAM, ROM, flash memory, etc.), optical storage media (e.g., CD-ROM), magnetic storage media (e.g., computer hard drives, floppy disks, etc.), punch cards, or other commercially available media. Information may be transferred between a system of interest and a medium, between computers, or between computers and the computer-readable medium for storage or access of stored information. Such transmission can be electrical, or by other available methods, such as IR links, wireless connections, etc.

A “nucleic acid sample”, as described herein, refers to a sample obtained from an individuals that contains nucleic acid. In certain embodiments, i.e. the detection of specific polymorphic markers and/or haplotypes, the nucleic acid sample comprises genomic DNA. Such a nucleic acid sample can be obtained from any source that contains genomic DNA, including as a blood sample, sample of amniotic fluid, sample of cerebrospinal fluid, or tissue sample from skin, muscle, buccal or conjunctival mucosa, placenta, gastrointestinal tract or other organs.

The term “CAD and/or MI therapeutic agent”, as described herein, refers to an agent that can be used to ameliorate or prevent symptoms associated with coronary artery disease or myocardial infarction. Such agents can for example be statins, beta blockers, calcium channel blockers, cardiac glycosides, antihypertensive agents, diuretics, agents acting on the renin-angiotensin system, and aspirin, or other therapeutic agents as described herein.

The term “CAD and/or MI-associated nucleic acid”, as described herein, refers to a nucleic acid that has been found to be associated to coronary artery disease and myocardial infarction. This includes, but is not limited to, the markers and haplotypes described herein and markers and haplotypes in linkage disequilibrium (LD) therewith.

The term “early onset”, as described herein, refers to onset of a disease that is lower than is typically observed. Fore example, in certain embodiments as applied to the MI phenotype, “early onset” can be defined as a MI event before the age of 50 for males and before the age of 60 for females. However, the term can be defined using other age cutoffs, as is deemed appropriate by the skilled person, and should in the present context be taken to mean age of onset of the disease that is lower than one would typically observe, and consequently considered early.

Association of Genetic Variants to Coronary Artery Disease and Myocardial Infarction

Through a genome-wide association search for variants contributing to increased risk of developing coronary artery disease (CAD) and myocardial infarction (MI), a number of SNP variants have been found to be associated with MI and CAD. These variants, (see Table 1), and variants in linkage disequilibrium with the identified variants, can be used to assess risk of developing CAD or MI in an individual, by determining the genotype of the individual for the individual variants. Haplotypes comprising the variants of the present invention, or haplotypes in LD with the variants of the invention, can also be used to assess risk of developing CAD or MI.

The genome-wide scan was expanded to a larger discovery cohort and the analysis repeated (Table 3). Most of the SNPs showing association in the discovery sample were investigated in six replication cohorts, from Durham (NC), Atlanta (GA), Philadelphia (PA), and Johns Hopkins (MD) in the United States, from Italy and from the Wellcome Trust Case Control Consortium (WTCCC). As shown in Table 4, several variants show evidence for association in the replication samples, in particular markers rs11751605, rs6076623, rs1412444, rs2163612 and rs1029396. These markers are therefore particularly useful in the methods, uses, apparatus and kits described further herein. The association of marker rs11751605 is particularly significant; the overall P-value of association for this marker to CAD is 1.16×10⁻⁸, which is genome-wide significant after correcting for the number of tests performed (Bonferroni correction gives 0.05/300,000˜1.7×10⁻⁷).

Markers in linkage disequilibrium with any one of rs11751605, rs6076623, rs1412444, rs2163612 and rs1029396 are also useful in the methods, uses, kits and apparatus of the invention. Markers in LD with rs11751605 are particularly useful. Surrogate markers for rs11751605, based on r² values in the Hapmap Caucasian CEU sample of greater than 0.2).

The marker rs11751605 is located on Chromosome 6, near the 5′ end of the Lipoprotein(a) gene (also called Lp(a)). The Lp(a) gene encodes a lipoprotein in a subclass consisting of an LDL-like particle and the specific apolipoprotein(a) [apo(a)], which is covalently bound to the apoB of the LDL-like particle.

Apo(a) proteins vary in size due to a size polymorphism [KIV-2 VNTR], which is caused by a variable number of so called kringle IV repeats in the LPA gene. These variable apo(a) sizes are known as “apo(a) isoforms”. There is a general inverse correlation between the size of the apo(a) isoform and the Lp(a) plasma concentration

Lp(a) concentrations are highly heritable and vary over one thousandfold between individuals, from <0.2 to >200 mg/dL. Lp(a) plasma concentrations is mainly controlled by the apolipoprotein(a) gene (LPA) located on chromosome 6q26-27. However, the apo(a) size polymorphism does not explain all the interindividual variation in Lp(a) levels in plasma. For alleles with identical number of K IV repeats, the Lp(a) level can vary by a factor of 200. Additional polymorphisms (independent from the K IV size polymorphism) in the gene have been shown to affect the Lp(a) concentration (Human Molecular Genetics, 2001, 10: 815-824). Therefore, the genetic determination of Lp(a) levels is highly complex and currently not fully understood.

Lipoprotein structure is similar to plasminogen and tPA (tissue plasminogen activator) and it has been shown to affect (reduce) fibrinolysis and (increase) thrombogenesis. In addition, the LDL cholesterol content of Lp-a contributes to atherosclerosis.

High Lp(a) in blood has been shown to be a risk factor for coronary heart disease (CHD), cerebrovascular disease (CVD), atherosclerosis, thrombosis, and stroke. However, few reported studies have investigated the association between genetic variants that affect Lp(a) concentration and coronary artery disease. The frequency of small apo(a) isoforms has been shown to be higher in patients with myocardial infarction compared with healthy controls (Atheroslerosis 144:323-333 (1999)) and another study has shown the isoforms to be higher in those with advanced atherosclerosis of the carotid arteries compared to those without advanced atherosclerosis (Circulation 100:1154-1160 (1999)).

A recent study reported that a single nucleotide polymorphism (rs3798220) in the coding sequence of the LPA gene associated with severe coronary artery disease and Lp(a) levels (Arterioscler Thromb Vasc Biol 27:2030-2036 (2007)). The rs11751605 marker is however not correlated with rs3798220. In a sample of over 5000 Icelanders genotyped for both markers, the at-risk allele of rs3798220 does not lie on the haplotype background of the risk allele rs11751605 (r²=0.002). In other words, the at-risk allele of rs3798220 and the at-risk allele of rs11751605 reside on different chromosomal backgrounds, and they are thus not inherited together. As a consequence, these signals are unrelated. The allelic frequency of rs11751605 allele C (the at-risk allele) is 11%, the frequency of rs3798220 allele C (the reported at-risk allele) is 1.5%, whereas their joint frequency is zero.

Thus, the association observed for rs11751605 is clearly not due to, or correlated to, rs3798220. Moreover, the rs3798220 C allele found to associate with Lp(a) levels is very rare (1.5%), whereas the at-risk C allele of rs11751605 is relatively common (11%), thus explaining a higher proportion of the risk conferred by the variant for MI and CAD susceptibility. It is at present not known if the rs11751605 marker correlates with Lp(a) levels in plasma.

It is important to note that correlation of a certain disease (MI or CAD, for example) to certain biological risk factors (biomarkers or related traits) does not, in general translate into association of the disease to markers in the gene encoding the biomarker. Moreover, genetic risk for a confounding trait or disease, or a known risk factor for a disease, does not necessarily translate into shared genetic effects. Many such examples are known from diseases such as type 2 diabetes, LDL cholesterol and obesity, which all have observable effects on the risk of CAD. For example, the strongest genetic risk factor for type II diabetes (in the TCF7L2 gene) does not show any association with MI. The markers rs693 and rs562338, located within the ApoB locus, have been shown to strongly correlate with LDL cholesterol levels (Nature Genet. 40:161-9 (2008)), yet these markers do not show any association with CAD. In addition, genetic markers within the FTO gene that have been shown to associate with obesity are not associated with CAD.

Thus, even in light of the prior knowledge of the correlation of Lp(a) levels with risk of CAD and MI, and the identification of genetic variants within the Lp(a) gene with Lp(a) levels, it would by no means have been obvious that genetic variants within the gene confer risk of MI or CAD. If this were the case, such a genetic relationship would presumably have been established much earlier. The present finding of an association between rs11751605 and risk of CAD and MI is thus very surprising.

Assessment for Markers and Haplotypes

The genomic sequence within populations is not identical when individuals are compared. Rather, the genome exhibits sequence variability between individuals at many locations in the genome. Such variations in sequence are commonly referred to as polymorphisms, and there are many such sites within each genome. For example, the human genome exhibits sequence variations which occur on average every 500 base pairs. The most common sequence variant consists of base variations at a single base position in the genome, and such sequence variants, or polymorphisms, are commonly called Single Nucleotide Polymorphisms (“SNPs”). These SNPs are believed to have occurred in a single mutational event, and therefore there are usually two possible alleles possible at each SNPsite; the original allele and the mutated allele. Due to natural genetic drift and possibly also selective pressure, the original mutation has resulted in a polymorphism characterized by a particular frequency of its alleles in any given population. Many other types of sequence variants are found in the human genome, including microsatellites, insertions, deletions, inversions and copy number variations. A polymorphic microsatellite has multiple small repeats of bases (such as CA repeats, TG on the complimentary strand) at a particular site in which the number of repeat lengths varies in the general population. In general terms, each version of the sequence with respect to the polymorphic site represents a specific allele of the polymorphic site. These sequence variants can all be referred to as polymorphisms, occurring at specific polymorphic sites characteristic of the sequence variant in question. In general terms, polymorphisms can comprise any number of specific alleles. Thus in one embodiment of the invention, the polymorphism is characterized by the presence of two or more alleles in any given population. In another embodiment, the polymorphism is characterized by the presence of three or more alleles. In other embodiments, the polymorphism is characterized by four or more alleles, five or more alleles, six or more alleles, seven or more alleles, nine or more alleles, or ten or more alleles. All such polymorphisms can be utilized in the methods and kits of the present invention, and are thus within the scope of the invention.

In some instances, reference is made to different alleles at a polymorphic site without choosing a reference allele. Alternatively, a reference sequence can be referred to for a particular polymorphic site. The reference allele is sometimes referred to as the “wild-type” allele and it usually is chosen as either the first sequenced allele or as the allele from a “non-affected” individual (e.g., an individual that does not display a trait or disease phenotype). Alleles for SNP markers as referred to herein refer to the bases A, C, G or T as they occur at the polymorphic site in the SNP assay employed. The allele codes for SNPs used herein are as follows: 1=A, 2=C, 3=G, 4=T. The person skilled in the art will however realise that by assaying or reading the opposite DNA strand, the complementary allele can in each case be measured. Thus, for a polymorphic site (polymorphic marker) containing an A/G polymorphism, the assay employed may either measure the percentage or ratio of the two bases possible, i.e. A and G. Alternatively, by designing an assay that determines the opposite strand on the DNA template, the percentage or ratio of the complementary bases T/C can be measured. Quantitatively (for example, in terms of relative risk), identical results would be obtained from measurement of either DNA strand (+strand or −strand).

Typically, a reference sequence is referred to for a particular sequence. Alleles that differ from the reference are referred to as “variant” alleles. A variant sequence, as used herein, refers to a sequence that differs from the reference sequence but is otherwise substantially similar. Alleles at the polymorphic genetic markers that make up the haplotypes described herein are variants. Additional variants can include changes that affect a polypeptide. Sequence differences, when compared to a reference nucleotide sequence, can include the insertion or deletion of a single nucleotide, or of more than one nucleotide, resulting in a frame shift; the change of at least one nucleotide, resulting in a change in the encoded amino acid; the change of at least one nucleotide, resulting in the generation of a premature stop codon; the deletion of several nucleotides, resulting in a deletion of one or more amino acids encoded by the nucleotides; the insertion of one or several nucleotides, such as by unequal recombination or gene conversion, resulting in an interruption of the coding sequence of a reading frame; duplication of all or a part of a sequence; transposition; or a rearrangement of a nucleotide sequence, as described in detail herein. Such sequence changes alter the polypeptide encoded by the nucleic acid. For example, if the change in the nucleic acid sequence causes a frame shift, the frame shift can result in a change in the encoded amino acids, and/or can result in the generation of a premature stop codon, causing generation of a truncated polypeptide. Alternatively, a polymorphism associated with coronary artery disease and myocardial infarction or a susceptibility to coronary artery disease and myocardial infarction can be a synonymous change in one or more nucleotides (i.e., a change that does not result in a change in the amino acid sequence). Such a polymorphism can, for example, alter splice sites, affect the stability or transport of mRNA, or otherwise affect the transcription or translation of an encoded polypeptide. It can also alter DNA to increase the possibility that structural changes, such as amplifications or deletions, occur at the somatic level. The polypeptide encoded by the reference nucleotide sequence is the “reference” polypeptide with a particular reference amino acid sequence, and polypeptides encoded by variant alleles are referred to as “variant” polypeptides with variant amino acid sequences.

A haplotype refers to a segment of DNA that is characterized by a specific combination of alleles arranged along the segment. For diploid organisms such as humans, a haplotype comprises one member of the pair of alleles for each polymorphic marker or locus. In a certain embodiment, the haplotype can comprise two or more alleles, three or more alleles, four or more alleles, or five or more alleles, each allele corresponding to a specific polymorphic marker along the segment. Haplotypes can comprise a combination of various polymorphic markers, e.g., SNPs and microsatellites, having particular alleles at the polymorphic sites. The haplotypes thus comprise a combination of alleles at various genetic markers.

Detecting specific polymorphic markers and/or haplotypes can be accomplished by methods known in the art for detecting sequences at polymorphic sites. For example, standard techniques for genotyping for the presence of SNPs and/or microsatellite markers can be used, such as fluorescence-based techniques (e.g., Chen, X. et al., Genome Res. 9(5): 492-98 (1999); Kutyavin et al., Nucleic Acid Res. 34:e128 (2006)), utilizing PCR, LCR, Nested PCR and other techniques for nucleic acid amplification. Specific methodologies available for SNP genotyping include, but are not limited to, TaqMan genotyping assays and SNPlex platforms (Applied Biosystems), mass spectrometry (e.g., MassARRAY system from Sequenom), minisequencing methods, real-time PCR, Bio-Plex system (BioRad), CEQ and SNPstream systems (Beckman), Molecular Inversion Probe array technology (e.g., Affymetrix GeneChip), and BeadArray Technologies (e.g., Illumina GoldenGate and Infinium assays). By these or other methods available to the person skilled in the art, one or more alleles at polymorphic markers, including microsatellites, SNPs or other types of polymorphic markers, can be identified.

In certain methods described herein, an individual who is at an increased susceptibility (i.e., at risk) for Coronary Artery Disease and myocardial infarction is an individual in whom at least one specific allele at one or more polymorphic marker or haplotype conferring increased susceptibility for Coronary Artery Disease and myocardial infarction is identified (i.e., at-risk marker alleles or haplotypes). In one aspect, the at-risk marker or haplotype is one that confers a significant increased risk (or susceptibility) of coronary artery disease and myocardial infarction. In one embodiment, significance associated with a marker or haplotype is measured by a relative risk (RR). In another embodiment, significance associated with a marker or haplotype is measured by an odds ratio (OR). In a further embodiment, the significance is measured by a percentage. In one embodiment, a significant increased risk is measured as a risk (relative risk and/or odds ratio) of at least 1.2, including but not limited to: at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, 1.8, at least 1.9, at least 2.0, at least 2.5, at least 3.0, at least 4.0, and at least 5.0. In a particular embodiment, a risk (relative risk and/or odds ratio) of at least 1.2 is significant. In another particular embodiment, a risk of at least 1.3 is significant. In yet another embodiment, a risk of at least 1.4 is significant. In a further embodiment, a relative risk of at least 1.5 is significant. In another further embodiment, a significant increase in risk is at least 1.7 is significant. However, other cutoffs are also contemplated, e.g., at least 1.15, 1.25, 1.35, and so on, and such cutoffs are also within scope of the present invention. In other embodiments, a significant increase in risk is at least about 20%, including but not limited to about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, and 500%. In one particular embodiment, a significant increase in risk is at least 20%. In other embodiments, a significant increase in risk is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% and at least 100%. Other cutoffs or ranges as deemed suitable by the person skilled in the art to characterize the invention are however also contemplated, and those are also within scope of the present invention. In certain embodiments, a significant increase in risk is characterized by a p-value, such as a p-value of less than 0.05, less than 0.01, less than 0.001, less than 0.0001, less than 0.00001, less than 0.000001, less than 0.0000001, less than 0.00000001, or less than 0.000000001.

An at-risk polymorphic marker or haplotype of the present invention is one where at least one allele of at least one marker or haplotype is more frequently present in an individual at risk for the disease or trait (affected), compared to the frequency of its presence in a comparison group (control), and wherein the presence of the marker or haplotype is indicative of susceptibility to coronary artery disease and/or myocardial infarction. The control group may in one embodiment be a population sample, i.e. a random sample from the general population. In another embodiment, the control group is represented by a group of individuals who are disease-free. Such disease-free control may in one embodiment be characterized by the absence of one or more specific disease-associated symptoms. In another embodiment, the disease-free control group is characterized by the absence of one or more disease-specific risk factors. Such risk factors are in one embodiment at least one environmental risk factor. Representative environmental factors are natural products, minerals or other chemicals which are known to affect, or contemplated to affect, the risk of developing the specific disease or trait. Other environmental risk factors are risk factors related to lifestyle, including but not limited to food and drink habits, geographical location of main habitat, and occupational risk factors. In another embodiment, the risk factors comprise at least one additional genetic risk factor.

As an example of a simple test for correlation would be a Fisher-exact test on a two by two table. Given a cohort of chromosomes, the two by two table is constructed out of the number of chromosomes that include both of the markers or haplotypes, one of the markers or haplotypes but not the other and neither of the markers or haplotypes. Other statistical tests of association known to the skilled person are also contemplated and are also within scope of the invention.

In other embodiments of the invention, an individual who is at a decreased susceptibility (i.e., at a decreased risk) for coronary artery disease and/or myocardial infarction is an individual in whom at least one specific allele at one or more polymorphic marker or haplotype conferring decreased susceptibility for coronary artery disease and myocardial infarction is identified. The marker alleles and/or haplotypes conferring decreased risk are also said to be protective. In one aspect, the protective marker or haplotype is one that confers a significant decreased risk (or susceptibility) of coronary artery disease and myocardial infarction. In one embodiment, significant decreased risk is measured as a relative risk (or odds ratio) of less than 0.9, including but not limited to less than 0.9, less than 0.8, less than 0.7, less than 0.6, less than 0.5, less than 0.4, less than 0.3, less than 0.2 and less than 0.1. In one particular embodiment, significant decreased risk is less than 0.7. In another embodiment, significant decreased risk is less than 0.5. In yet another embodiment, significant decreased risk is less than 0.3. In another embodiment, the decrease in risk (or susceptibility) is at least 20%, including but not limited to at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% and at least 98%. In one particular embodiment, a significant decrease in risk is at least about 30%. In another embodiment, a significant decrease in risk is at least about 50%. In another embodiment, the decrease in risk is at least about 70%. Other cutoffs or ranges as deemed suitable by the person skilled in the art to characterize the invention are however also contemplated, and those are also within scope of the present invention.

The person skilled in the art will appreciate that for markers with two alleles present in the population being studied (such as SNPs), and wherein one allele is found in increased frequency in a group of individuals with a trait or disease in the population, compared with controls, the other allele of the marker will be found in decreased frequency in the group of individuals with the trait or disease, compared with controls. In such a case, one allele of the marker (the one found in increased frequency in individuals with the trait or disease) will be the at-risk allele, while the other allele will be a protective allele.

A genetic variant associated with a disease or a trait (e.g. CAD or MI) can be used alone to predict the risk of the disease for a given genotype. For a biallelic marker, such as a SNP, there are 3 possible genotypes: homozygote for the at risk variant, heterozygote, and non carrier of the at risk variant. Risk associated with variants at multiple loci can be used to estimate overall risk. For multiple SNP variants, there are k possible genotypes k=3^(n)×2^(p); where n is the number autosomal loci and p the number of gonosomal (sex chromosomal) loci. Overall risk assessment calculations usually assume that the relative risks of different genetic variants multiply, i.e. the overall risk (e.g., RR or OR) associated with a particular genotype combination is the product of the risk values for the genotype at each locus. If the risk presented is the relative risk for a person, or a specific genotype for a person, compared to a reference population with matched gender and ethnicity, then the combined risk—is the product of the locus specific risk values—and which also corresponds to an overall risk estimate compared with the population. If the risk for a person is based on a comparison to non-carriers of the at risk allele, then the combined risk corresponds to an estimate that compares the person with a given combination of genotypes at all loci to a group of individuals who do not carry risk variants at any of those loci. The group of non-carriers of any at risk variant has the lowest estimated risk and has a combined risk, compared with itself (i.e., non-carriers) of 1.0, but has an overall risk, compare with the population, of less than 1.0. It should be noted that the group of non-carriers can potentially be very small, especially for large number of loci, and in that case, its relevance is correspondingly small.

The multiplicative model is a parsimonious model that usually fits the data of complex traits reasonably well. Deviations from multiplicity have been rarely described in the context of common variants for common diseases, and if reported are usually only suggestive since very large sample sizes are usually required to be able to demonstrate statistical interactions between loci.

By way of an example, let us consider a total of eight variants that have been described to associate with prostate cancer (Gudmundsson, J., et al., Nat Genet 39:631-7 (2007), Gudmundsson, J., et al., Nat Genet 39:977-83 (2007); Yeager, M., et al, Nat Genet 39:645-49 (2007), Amundadottir, L., et al., Nat Genet 38:652-8 (2006); Haiman, C. A., et al., Nat Genet 39:638-44 (2007)). Seven of these loci are on autosomes, and the remaining locus is on chromosome X. The total number of theoretical genotypic combinations is then 3⁷×2¹=4374. Some of those genotypic classes are very rare, but are still possible, and should be considered for overall risk assessment. It is likely that the multiplicative model applied in the case of multiple genetic variant will also be valid in conjugation with non-genetic risk variants assuming that the genetic variant does not clearly correlate with the “environmental” factor. In other words, genetic and non-genetic at-risk variants can be assessed under the multiplicative model to estimate combined risk, assuming that the non-genetic and genetic risk factors do not interact.

Using the same quantitative approach, the combined or overall risk associated with a plurality of variants associated with CAD and MI may be assessed. In certain such embodiments, the markers described herein are assessed together with at least one marker in linkage disequilibrium with the CDKN2A and/or CDKN2A genes, such as rs10811650, rs10116277, rs1333040, rs10738607, rs4977574, rs6475608, D9S1870, rs2383207, rs1333045, rs1333046, rs10757278 or rs1333048. In a preferred embodiment, the markers described herein are assessed in combination with rs10757278.

Linkage Disequilibrium

The natural phenomenon of recombination, which occurs on average once for each chromosomal pair during each meiotic event, represents one way in which nature provides variations in sequence (and biological function by consequence). It has been discovered that recombination does not occur randomly in the genome; rather, there are large variations in the frequency of recombination rates, resulting in small regions of high recombination frequency (also called recombination hotspots) and larger regions of low recombination frequency, which are commonly referred to as Linkage Disequilibrium (LD) blocks (Myers, S. et al., Biochem Soc Trans 34:526-530 (2006); Jeffreys, A. J., et al., Nature Genet 29:217-222 (2001); May, C. A., et al., Nature Genet 31:272-275 (2002)).

Linkage Disequilibrium (LD) refers to a non-random assortment of two genetic elements. For example, if a particular genetic element (e.g., “alleles” of a polymorphic marker) occurs in a population at a frequency of 0.50 (50%) and another occurs at a frequency of 0.50 (50%), then the predicted occurrence of a person's having both elements is 0.25 (25%), assuming a random distribution of the elements. However, if it is discovered that the two elements occur together at a frequency higher than 0.25, then the elements are said to be in linkage disequilibrium since they tend to be inherited together at a higher rate than what their independent allele frequencies would predict. Roughly speaking, LD is generally correlated with the frequency of recombination events between the two elements. Allele frequencies can be determined in a population by genotyping individuals in a population and determining the occurrence of each allele in the population. For populations of diploids, e.g., human populations, individuals will typically have two alleles for each genetic element (e.g., a marker or gene).

Many different measures have been proposed for assessing the strength of linkage disequilibrium (LD). Most capture the strength of association between pairs of biallelic sites. Two important pairwise measures of LD are r² (sometimes denoted Δ²) and |D′|. Both measures range from 0 (no disequilibrium) to 1 (‘complete’ disequilibrium), but their interpretation is slightly different. |D′| is defined in such a way that it is equal to 1 if just two or three of the possible haplotypes are present, and it is <1 if all four possible haplotypes are present. So, a value of |D′| that is <1 indicates that historical recombination may have occurred between two sites (recurrent mutation can also cause |D′| to be <1, but for single nucleotide polymorphisms (SNPs) this is usually regarded as being less likely than recombination). The measure r² represents the statistical correlation between two sites, and takes the value of 1 if only two haplotypes are present.

The r² measure is arguably the most relevant measure for association mapping, because there is a simple inverse relationship between r² and the sample size required to detect association between susceptibility loci and SNPs. These measures are defined for pairs of sites, but for some applications a determination of how strong LD is across an entire region that contains many polymorphic sites might be desirable (e.g., testing whether the strength of LD differs significantly among loci or across populations, or whether there is more or less LD in a region than predicted under a particular model). Measuring LD across a region is not straightforward, but one approach is to use the measure r, which was developed in population genetics. Roughly speaking, r measures how much recombination would be required under a particular population model to generate the LD that is seen in the data. This type of method can potentially also provide a statistically rigorous approach to the problem of determining whether LD data provide evidence for the presence of recombination hotspots. For the methods described herein, a significant r² value can be at least 0.1 such as at least 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, or at least 0.99. In one preferred embodiment, the significant r² value can be at least 0.2. Alternatively, linkage disequilibrium as described herein, refers to linkage disequilibrium characterized by values of |D′| of at least 0.2, such as 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.85, 0.9, 0.95, 0.96, 0.97, 0.98, or at least 0.99. Thus, linkage disequilibrium represents a correlation between alleles of distinct markers. It is measured by correlation coefficient or |D′| (r² up to 1.0 and |D′| up to 1.0). In certain embodiments, linkage disequilibrium is defined in terms of values for both the r² and |D′| measures. In one such embodiment, a significant linkage disequilibrium is defined as r²>0.1 and |D′|>0.8. In another embodiment, a significant linkage disequilibrium is defined as r²>0.2 and |D′|>0.9. Other combinations and permutations of values of r² and |D′| for determining linkage disequilibrium are also contemplated, and are also within the scope of the invention. Linkage disequilibrium can be determined in a single human population, as defined herein, or it can be determined in a collection of samples comprising individuals from more than one human population. In one embodiment of the invention, LD is determined in a sample from one or more of the HapMap populations (caucasian, african, japanese, chinese), as defined (http://www.hapmap.org). In one such embodiment, LD is determined in the Caucasian CEU population of the HapMap samples. In another embodiment, LD is determined in the African YRI population. In yet another embodiment, LD is determined in samples from the Icelandic population.

If all polymorphisms in the genome were independent at the population level (i.e., no LD), then every single one of them would need to be investigated in association studies, to assess all the different polymorphic states. However, due to linkage disequilibrium between polymorphisms, tightly linked polymorphisms are strongly correlated, which reduces the number of polymorphisms that need to be investigated in an association study to observe a significant association. Another consequence of LD is that many polymorphisms may give an association signal due to the fact that these polymorphisms are strongly correlated.

Genomic LD maps have been generated across the genome, and such LD maps have been proposed to serve as framework for mapping disease-genes (Risch, N. & Merkiangas, K, Science 273:1516-1517 (1996); Maniatis, N., et al., Proc Natl Acad Sci USA 99:2228-2233 (2002); Reich, D E et al, Nature 411:199-204 (2001)).

It is now established that many portions of the human genome can be broken into series of discrete haplotype blocks containing a few common haplotypes; for these blocks, linkage disequilibrium data provides little evidence indicating recombination (see, e.g., Wall., J. D. and Pritchard, J. K., Nature Reviews Genetics 4:587-597 (2003); Daly, M. et al., Nature Genet. 29:229-232 (2001); Gabriel, S. B. et al., Science 296:2225-2229 (2002); Patil, N. et al., Science 294:1719-1723 (2001); Dawson, E. et al., Nature 418:544-548 (2002); Phillips, M. S. et al., Nature Genet. 33:382-387 (2003)).

There are two main methods for defining these haplotype blocks: blocks can be defined as regions of DNA that have limited haplotype diversity (see, e.g., Daly, M. et al., Nature Genet. 29:229-232 (2001); Patil, N. et al., Science 294:1719-1723 (2001); Dawson, E. et al., Nature 418:544-548 (2002); Zhang, K. et al., Proc. Natl. Acad. Sci. USA 99:7335-7339 (2002)), or as regions between transition zones having extensive historical recombination, identified using linkage disequilibrium (see, e.g., Gabriel, S. B. et al., Science 296:2225-2229 (2002); Phillips, M. S. et al., Nature Genet. 33:382-387 (2003); Wang, N. et al., Am. J. Hum. Genet. 71:1227-1234 (2002); Stumpf, M. P., and Goldstein, D. B., Curr. Biol. 13:1-8 (2003)). More recently, a fine-scale map of recombination rates and corresponding hotspots across the human genome has been generated (Myers, S., et al., Science 310:321-32324 (2005); Myers, S. et al., Biochem Soc Trans 34:526530 (2006)). The map reveals the enormous variation in recombination across the genome, with recombination rates as high as 10-60 cM/Mb in hotspots, while closer to 0 in intervening regions, which thus represent regions of limited haplotype diversity and high LD. The map can therefore be used to define haplotype blocks/LD blocks as regions flanked by recombination hotspots. As used herein, the terms “haplotype block” or “LD block” includes blocks defined by any of the above described characteristics, or other alternative methods used by the person skilled in the art to define such regions.

Haplotype blocks (LD blocks) can be used to map associations between phenotype and haplotype status, using single markers or haplotypes comprising a plurality of markers. The main haplotypes can be identified in each haplotype block, and then a set of “tagging” SNPs or markers (the smallest set of SNPs or markers needed to distinguish among the haplotypes) can then be identified. These tagging SNPs or markers can then be used in assessment of samples from groups of individuals, in order to identify association between phenotype and haplotype. If desired, neighboring haplotype blocks can be assessed concurrently, as there may also exist linkage disequilibrium among the haplotype blocks.

It has thus become apparent that for any given observed association to a polymorphic marker in the genome, it is likely that additional markers in the genome also show association. This is a natural consequence of the uneven distribution of LD across the genome, as observed by the large variation in recombination rates. The markers used to detect association thus in a sense represent “tags” for a genomic region (i.e., a haplotype block or LD block) that is associating with a given disease or trait, and as such are useful for use in the methods and kits of the present invention. One or more causative (functional) variants or mutations may reside within the region found to be associating to the disease or trait. Such variants may confer a higher relative risk (RR) or odds ratio (OR) than observed for the tagging markers used to detect the association. The present invention thus refers to the markers used for detecting association to the disease, as described herein, as well as markers in linkage disequilibrium with the markers. Thus, in certain embodiments of the invention, markers that are in LD with the markers and/or haplotypes of the invention, as described herein, may be used as surrogate markers. The surrogate markers have in one embodiment relative risk (RR) and/or odds ratio (OR) values smaller than for the markers or haplotypes initially found to be associating with the disease, as described herein. In other embodiments, the surrogate markers have RR or OR values greater than those initially determined for the markers initially found to be associating with the disease, as described herein. An example of such an embodiment would be a rare, or relatively rare (such as <10% allelic population frequency) variant in LD with a more common variant (>10% population frequency) initially found to be associating with the disease, such as the variants described herein. Identifying and using such markers for detecting the association discovered by the inventors as described herein can be performed by routine methods well known to the person skilled in the art, and are therefore within the scope of the present invention.

Determination of Haplotype Frequency

The frequencies of haplotypes in patient and control groups can be estimated using an expectation-maximization algorithm (Dempster A. et al., J. R. Stat. Soc. B, 39:1-38 (1977)). An implementation of this algorithm that can handle missing genotypes and uncertainty with the phase can be used. Under the null hypothesis, the patients and the controls are assumed to have identical frequencies. Using a likelihood approach, an alternative hypothesis is tested, where a candidate at-risk-haplotype, which can include the markers described herein, is allowed to have a higher frequency in patients than controls, while the ratios of the frequencies of other haplotypes are assumed to be the same in both groups. Likelihoods are maximized separately under both hypotheses and a corresponding 1-df likelihood ratio statistic is used to evaluate the statistical significance.

To look for at-risk and protective markers and haplotypes within a linkage region, for example, association of all possible combinations of genotyped markers is studied, provided those markers span a practical region. The combined patient and control groups can be randomly divided into two sets, equal in size to the original group of patients and controls. The marker and haplotype analysis is then repeated and the most significant p-value registered is determined. This randomization scheme can be repeated, for example, over 100 times to construct an empirical distribution of p-values. In a preferred embodiment, a p-value of <0.05 is indicative of an significant marker and/or haplotype association.

Haplotype Analysis

One general approach to haplotype analysis involves using likelihood-based inference applied to NEsted MOdels (Gretarsdottir S., et al., Nat. Genet. 35:131-38 (2003)). The method is implemented in the program NEMO, which allows for many polymorphic markers, SNPs and microsatellites. The method and software are specifically designed for case-control studies where the purpose is to identify haplotype groups that confer different risks. It is also a tool for studying LD structures. In NEMO, maximum likelihood estimates, likelihood ratios and p-values are calculated directly, with the aid of the EM algorithm, for the observed data treating it as a missing-data problem.

Even though likelihood ratio tests based on likelihoods computed directly for the observed data, which have captured the information loss due to uncertainty in phase and missing genotypes, can be relied on to give valid p-values, it would still be of interest to know how much information had been lost due to the information being incomplete. The information measure for haplotype analysis is described in Nicolae and Kong (Technical Report 537, Department of Statistics, University of Statistics, University of Chicago; Biometrics, 60(2):368-75 (2004)) as a natural extension of information measures defined for linkage analysis, and is implemented in NEMO.

For single marker association to a disease, the Fisher exact test can be used to calculate two-sided p-values for each individual allele. Usually, all p-values are presented unadjusted for multiple comparisons unless specifically indicated. The presented frequencies (for microsatellites, SNPs and haplotypes) are allelic frequencies as opposed to carrier frequencies. To minimize any bias due the relatedness of the patients who were recruited as families for the linkage analysis, first and second-degree relatives can be eliminated from the patient list. Furthermore, the test can be repeated for association correcting for any remaining relatedness among the patients, by extending a variance adjustment procedure described in Risch, N. & Teng, J. (Genome Res., 8:1273-1288 (1998)), DNA pooling (ibid) for sibships so that it can be applied to general familial relationships, and present both adjusted and unadjusted p-values for comparison. The differences are in general very small as expected. To assess the significance of single-marker association corrected for multiple testing we can carry out a randomization test using the same genotype data. Cohorts of patients and controls can be randomized and the association analysis redone multiple times (e.g., up to 500,000 times) and the p-value is the fraction of replications that produced a p-value for some marker allele that is lower than or equal to the p-value we observed using the original patient and control cohorts. Alternatively, a test of association is done in one or several additional case-control cohorts in replication analyses. For tests of single markers, a replication sample analysis only needs to fulfill nominal statistical significance of P<0.05 (two-sided testing; P<0.1 may in fact be more appropriate since a single predefined effect of a single marker is being tested). If many markers are tested in a replication effort, a correction for the number of markers tested in the replication analysis is performed. Alternatively, the results of replication in several case-control cohorts can be combined to provide an overall assessment of the underlying effect, and this may be the most appropriate way of testing the validity of the initially discovered association signal. Deficiencies in individual case-control comparisons, for example due to recruitment bias or population can be neutralized by combined analysis of several case-control studies. The most common method for performing such analysis is the Mantel Haenszel model, which allows different population frequencies for alleles, haplotypes and genotypes but assumes a common relative risk (Mantel, N. & Haenszel, W., J Natl Cancer Inst 22:719 (1959)).

For both single-marker and haplotype analyses, relative risk (RR) and the population attributable risk (PAR) can be calculated assuming a multiplicative model (haplotype relative risk model) (Terwilliger, J. D. & Ott, J., Hum. Hered. 42:337-46 (1992) and Falk, C. T. & Rubinstein, P, Ann. Hum. Genet. 51 (Pt 3):227-33 (1987)), i.e., that the risks of the two alleles/haplotypes a person carries multiply. For example, if RR is the risk of A relative to a, then the risk of a person homozygote AA will be RR times that of a heterozygote Aa and RR² times that of a homozygote aa. The multiplicative model has a nice property that simplifies analysis and computations—haplotypes are independent, i.e., in Hardy-Weinberg equilibrium, within the affected population as well as within the control population. As a consequence, haplotype counts of the affected and controls each have multinomial distributions, but with different haplotype frequencies under the alternative hypothesis. Specifically, for two haplotypes, h_(i) and h_(j), risk(h_(i))/risk(h_(j))=(f_(i)/p_(i))/(f_(j)/p_(j)), where f and p denote, respectively, frequencies in the affected population and in the control population. While there is some power loss if the true model is not multiplicative, the loss tends to be mild except for extreme cases. Most importantly, p-values are always valid since they are computed with respect to null hypothesis.

Linkage Disequilibrium Using NEMO

LD between pairs of markers can be calculated using the standard definition of D′ and r² (Lewontin, R., Genetics 49:49-67 (1964); Hill, W. G. & Robertson, A. Theor. Appl. Genet. 22:226-231 (1968)). Using NEMO, frequencies of the two marker allele combinations are estimated by maximum likelihood and deviation from linkage equilibrium is evaluated by a likelihood ratio test. The definitions of D′ and r² are extended to include microsatellites by averaging over the values for all possible allele combination of the two markers weighted by the marginal allele probabilities. When plotting all marker combination to elucidate the LD structure in a particular region, we plot D′ in the upper left corner and the p-value in the lower right corner. In the LD plots the markers can be plotted equidistant rather than according to their physical location, if desired.

Risk Assessment and Diagnostics

Within any given population, there is an absolute risk of developing a disease or trait, defined as the chance of a person developing the specific disease or trait over a specified time-period. For example, a woman's lifetime absolute risk of breast cancer is one in nine. That is to say, one woman in every nine will develop breast cancer at some point in their lives. Risk is typically measured by looking at very large numbers of people, rather than at a particular individual. Risk is often presented in terms of Absolute Risk (AR) and Relative Risk (RR). Relative Risk is used to compare risks associating with two variants or the risks of two different groups of people. For example, it can be used to compare a group of people with a certain genotype with another group having a different genotype. For a disease, a relative risk of 2 means that one group has twice the chance of developing a disease as the other group. The Risk presented is usually the relative risk for a person, or a specific genotype of a person, compared to the population with matched gender and ethnicity. Risks of two individuals of the same gender and ethnicity could be compared in a simple manner. For example, if, compared to the population, the first individual has relative risk 1.5 and the second has relative risk 0.5, then the risk of the first individual compared to the second individual is 1.5/0.5=3.

In certain embodiments, marker and haplotype analysis involves defining a candidate susceptibility region or locus based on “haplotype blocks” (also called “LD blocks”). It is now established that many portions of the human genome can be broken into series of discrete haplotype blocks containing a few common haplotypes; for these blocks, linkage disequilibrium data provides little evidence indicating recombination (see, e.g., Wall., J. D. and Pritchard, J. K., Nature Reviews Genetics 4:587-597 (2003); Daly, M. et al., Nature Genet. 29:229-232 (2001); Gabriel, S. B. et al., Science 296:2225-2229 (2002); Patil, N. et al., Science 294:1719-1723 (2001); Dawson, E. et al., Nature 418:544-548 (2002); Phillips, M. S. et al., Nature Genet. 33:382-387 (2003)).

There are two main methods for defining these haplotype blocks: blocks can be defined as regions of DNA that have limited haplotype diversity (see, e.g., Daly, M. et al., Nature Genet. 29:229-232 (2001); Patil, N. et al., Science 294:1719-1723 (2001); Dawson, E. et al., Nature 418:544-548 (2002); Zhang, K. et al., Proc. Natl. Acad. Sci. USA 99:7335-7339 (2002)), or as regions between transition zones having extensive historical recombination, identified using linkage disequilibrium (see, e.g., Gabriel, S. B. et al., Science 296:2225-2229 (2002); Phillips, M. S. et al., Nature Genet. 33:382-387 (2003); Wang, N. et al., Am. J. Hum. Genet. 71:1227-1234 (2002); Stumpf, M. P., and Goldstein, D. B., Curr. Biol. 13:1-8 (2003)). As used herein, the terms “haplotype block” or “LD block” includes blocks defined by either characteristic.

Representative methods for identification of haplotype blocks are set forth, for example, in U.S. Published Patent Application Nos. 20030099964, 20030170665, 20040023237 and 20040146870. Haplotype blocks can be used readily to map associations between phenotype and haplotype status. The main haplotypes can be identified in each haplotype block, and then a set of “tagging” SNPs or markers (the smallest set of SNPs or markers needed to distinguish among the haplotypes) can then be identified. These tagging SNPs or markers can then be used in assessment of samples from groups of individuals, in order to identify association between phenotype and haplotype. If desired, neighboring haplotype blocks can be assessed concurrently, as there may also exist linkage disequilibrium among the haplotype blocks.

As described herein, certain markers and haplotypes comprising such markers are found to be useful for risk assessment of cardiovascular disease, including coronary artery disease and myocardial infarction. Risk assessment can involve the use of the markers and variants for diagnosing a susceptibility to cardiovascular disease, including coronary artery disease and myocardial infarction. Particular alleles of polymorphic markers and haplotypes are found more frequently in individuals with cardiovascular disease, including coronary artery disease and myocardial infarction than in individuals without diagnosis of cardiovascular disease, including coronary artery disease and myocardial infarction. Therefore, these marker alleles and haplotypes have predictive value for detecting cardiovascular disease, including coronary artery disease and myocardial infarction, or a susceptibility to coronary artery disease and myocardial infarction, in an individual. Tagging markers within haplotype blocks or LD blocks comprising at-risk markers, such as the markers of the present invention, can be used as surrogates for other markers within the haplotype block or LD block. Markers with values of r² equal to 1 are perfect surrogates for the at-risk variants, i.e. genotypes for one marker perfectly predicts genotypes for the other. Markers with smaller values of r² than 1 can also be surrogates for the at-risk variant, or alternatively represent variants with relative risk values as high or possibly even higher than the at-risk variant. The at-risk variant identified may therefore not be the functional variant itself, but is in this instance in linkage disequilibrium with the true functional variant. The present invention encompasses the assessment of such surrogate markers for the markers as disclosed herein. Such markers are annotated, mapped and listed in public databases, as well known to the skilled person, or can alternatively be readily identified by sequencing the region or a part of the region identified by the markers of the present invention in a group of individuals, and identify polymorphisms in the resulting group of sequences. As a consequence, the person skilled in the art can readily and without undue experimentation genotype surrogate markers in linkage disequilibrium with the markers and/or haplotypes as described herein. The tagging or surrogate markers in LD with the at-risk variants detected also have predictive value for detecting association to CAD and/or MI, or a susceptibility to CAD and/or MI, in an individual. These tagging or surrogate markers that are in LD with the markers of the present invention can also include other markers that distinguish among haplotypes in associated genomic regions, as these similarly have predictive value for detecting susceptibility to CAD and MI.

The present invention can in certain embodiments be practiced by assessing a sample comprising genomic DNA from an individual for the presence of variants described herein to be associated with the cardiovascular diseases CAD and MI. Such assessment includes steps of detecting the presence or absence of at least one allele of at least one polymorphic marker, using methods well known to the skilled person and further described herein, and based on the outcome of such assessment, determine whether the individual from whom the sample is derived is at increased or decreased risk (increased or decreased susceptibility) of CAD and/or MI. Alternatively, the invention can be practiced utilizing a dataset comprising information about the genotype status of at least one polymorphic marker described herein to be associated with CAD and/or MI (or markers in linkage disequilibrium with at least one marker shown herein to be associated with CAD and/or MI). In other words, a dataset containing information about such genetic status, for example in the form of genotype counts at a certain polymorphic marker, or a plurality of markers (e.g., an indication of the presence or absence of certain at-risk alleles), or actual genotypes for one or more markers, can be queried for the presence or absence of certain at-risk alleles at certain polymorphic markers shown by the present inventors to be associated with CAD and/or MI. A positive result for a variant (e.g., marker allele) associated with CAD and/or MI, as shown herein, is indicative of the individual from which the dataset is derived is at increased susceptibility (increased risk) of CAD and/or MI.

In certain embodiments of the invention, a polymorphic marker is correlated to CAD and/or MI by referencing genotype data for the polymorphic marker to a look-up table that comprises correlations between at least one allele of the polymorphism and CAD and/or MI. In some embodiments, the table comprises a correlation for one polymorphism. In other embodiments, the table comprises a correlation for a plurality of polymorphisms. In both scenarios, by referencing to a look-up table that gives an indication of a correlation between a marker and CAD and/or MI, a risk for CAD and/or MI, or a susceptibility to CAD and/or MI, can be identified in the individual from whom the sample is derived. In some embodiments, the correlation is reported as a statistical measure. The statistical measure may be reported as a risk measure, such as a relative risk (RR), an absolute risk (AR) or an odds ratio (OR).

The markers and haplotypes of the invention, e.g., the markers presented in Table 4, may be useful for risk assessment and diagnostic purposes for coronary artery disease and myocardial infarction, either alone or in combination. Thus, even in the cases where the increase in risk by individual markers is relatively modest, i.e. on the order of 10-30%, the association may have significant implications. Thus, relatively common variants may have significant contribution to the overall risk (Population Attributable Risk is high), or combination of markers can be used to define groups of individual who, based on the combined risk of the markers, is at significant combined risk of developing CAD and/or MI. Thus, in one embodiment of the invention, a plurality of variants (markers and/or haplotypes) is used for overall risk assessment. In such embodiments, the genotype status of a plurality of markers and/or haplotypes is determined in an individual, and the status of the individual compared with the population frequency of the associated variants, or the frequency of the variants in clinically healthy subjects, such as age-matched and sex-matched subjects. Methods known in the art, such as multivariate analyses or joint risk analyses, may subsequently be used to determine the overall risk conferred based on the genotype status at the multiple loci. Assessment of risk based on such analysis may subsequently be used in the methods and kits of the invention, as described herein.

As described in the above, the haplotype block structure of the human genome has the effect that a large number of variants (markers and/or haplotypes) in linkage disequilibrium with the variant originally associated with a disease or trait may be used as surrogate markers for assessing association to the disease or trait. The number of such surrogate markers will depend on factors such as the historical recombination rate in the region, the mutational frequency in the region (i.e., the number of polymorphic sites or markers in the region), and the extent of LD (size of the LD block) in the region. These markers are usually located within the physical boundaries of the LD block or haplotype block in question as defined using the methods described herein, or by other methods known to the person skilled in the art. However, sometimes marker and haplotype association is found to extend beyond the physical boundaries of the haplotype block as defined. Such markers and/or haplotypes may in those cases be also used as surrogate markers and/or haplotypes for the markers and/or haplotypes physically residing within the haplotype block as defined. As a consequence, markers and haplotypes in LD (typically characterized by r² greater than 0.1, such as r² greater than 0.2, including r² greater than 0.3, also including r² greater than 0.4) with the markers and haplotypes of the present invention are also within the scope of the invention, even if they are physically located beyond the boundaries of the haplotype block as defined. This includes markers that are described herein (e.g., Table 4), but may also include other markers that are in strong LD (characterized by r² greater than 0.1 or 0.2 and/or |D′|>0.8) with one or more of the markers listed in Table 4.

For the SNP markers described herein, the opposite allele to the allele found to be in excess in patients (at-risk allele) is found in decreased frequency in coronary artery disease and myocardial infarction. These markers and haplotypes in LD and/or comprising such markers, are thus protective for coronary artery disease and myocardial infarction, i.e. they confer a decreased risk or susceptibility of individuals carrying these markers and/or haplotypes developing coronary artery disease and myocardial infarction.

Certain variants of the present invention, including certain haplotypes comprise, in some cases, a combination of various genetic markers, e.g., SNPs and microsatellites. Detecting haplotypes can be accomplished by methods known in the art and/or described herein for detecting sequences at polymorphic sites. Furthermore, correlation between certain haplotypes or sets of markers and disease phenotype can be verified using standard techniques. A representative example of a simple test for correlation would be a Fisher-exact test on a two by two table.

In specific embodiments, a marker allele or haplotype associated with coronary artery disease and myocardial infarction (e.g., marker alleles as listed in Table 4) is one in which the marker allele or haplotype is more frequently present in an individual at risk for coronary artery disease and/or myocardial infarction (affected), compared to the frequency of its presence in a healthy individual (control), wherein the presence of the marker allele or haplotype is indicative of coronary artery disease and/or myocardial infarction or a susceptibility to coronary artery disease and/or myocardial infarction. In other embodiments, at-risk markers in linkage disequilibrium with one or more markers found to be associated with coronary artery disease and/or myocardial infarction (e.g., marker alleles as listed in Table 4) are tagging markers that are more frequently present in an individual at risk for coronary artery disease and/or myocardial infarction (affected), compared to the frequency of their presence in a healthy individuals (controls), wherein the presence of the tagging markers is indicative of increased susceptibility to coronary artery disease and/or myocardial infarction. In a further embodiment, at-risk markers alleles (i.e. conferring increased susceptibility) in linkage disequilibrium with one or more markers found to be associated with coronary artery disease and/or myocardial infarction (e.g., marker alleles as listed in Table 4), are markers comprising one or more allele that is more frequently present in an individual at risk for coronary artery disease and/or myocardial infarction, compared to the frequency of their presence in a healthy individual (control), wherein the presence of the markers is indicative of increased susceptibility to coronary artery disease and/or myocardial infarction.

Utility of Genetic Testing

The person skilled in the art will appreciate and understand that the variants described herein in general do not, by themselves, provide an absolute identification of individuals who will develop coronary artery disease or myocardial infarction. The variants described herein do however indicate increased and/or decreased likelihood that individuals carrying the at-risk or protective variants of the invention will develop CAD or MI, or develop symptoms associated with these diseases. This information is however extremely valuable in itself, as outlined in more detail in the below, as it can be used to, for example, initiate preventive measures at an early stage, perform regular physical and/or mental exams to monitor the progress and/or appearance of symptoms, or to schedule exams at a regular interval to identify early symptoms, so as to be able to apply treatment at an early stage.

The knowledge about a genetic variant that confers a risk of developing cardiovascular disease, including coronary artery disease and myocardial infarction, offers the opportunity to apply a genetic test to distinguish between individuals with increased risk of developing the disease (i.e. carriers of the at-risk variant) and those with decreased risk of developing the disease (i.e. carriers of the protective variant). The core values of genetic testing, for individuals belonging to both of the above mentioned groups, are the possibilities of being able to diagnose disease, or a predisposition to disease, at an early stage and provide information to the clinician about prognosis/aggressiveness of disease in order to be able to apply the most appropriate treatment.

Individuals with a family history of CAD and/or MI and carriers of at-risk variants may benefit from genetic testing since the knowledge of the presence of a genetic risk factor, or evidence for increased risk of being a carrier of one or more risk factors, may provide increased incentive for implementing a healthier lifestyle (e.g., lose weight, increase exercise, give um smoking, reduce stress, etc.), by avoiding or minimizing known environmental risk factors for these cardiovascular diseases. Genetic testing of patients may furthermore give valuable information about the primary cause of the disease and can aid the clinician in selecting the best treatment options and medication for each individual.

The present invention can be thus be used for risk assessment for coronary artery disease and/or myocardial infarction, including diagnosing whether an individual is at risk for developing myocardial infarction and/or coronary artery disease. The polymorphic markers of the present invention can be used alone or in combination, as well as in combination with other factors, including known biomarkers, for risk assessment of an individual for coronary artery disease and/or myocardial infarction. Many factors known to affect the predisposition of individual towards developing risk of developing cardiovascular disease, including coronary artery disease and/or myocardial infarction, are known to the person skilled in the art and can be utilized in such assessment. These include, but are not limited to, age, gender, smoking status, physical activity, waist-to-hip circumference ratio, family history of Cardiovascular Disease (e.g., MI and/or CAD), previously diagnosed cardiovascular disease, obesity, diagnosis of Diabetes mellitus, stress, depression, elevated heart rate, hypertriglyceridemia, low HDL cholesterol, hypertension, elevated blood pressure, cholesterol levels, HDL cholesterol, LDL cholesterol, triglycerides, apolipoprotein AI and B levels, fibrinogen, ferritin, C-reactive protein and leukotriene levels. Methods known in the art can be used for such assessment, including multivariate analyses or logistic regression, as described further herein.

Methods

Methods for risk management and risk assessment of CAD and MI are described herein and are encompassed by the invention. The invention also encompasses methods of assessing an individual for probability of response to a therapeutic agent for a CAD and/or MI, methods for predicting the effectiveness of a therapeutic agent for CAD and/or MI, nucleic acids, polypeptides and antibodies and computer-implemented functions useful in such methods. Kits for assaying a sample from a subject to detect susceptibility to cardiovascular disease are also encompassed by the invention.

Diagnostic and Screening Methods

In certain embodiments, the present invention pertains to methods of diagnosing, or aiding in the diagnosis of coronary artery disease (CAD) and/or myocardial infarction (MI) or a susceptibility to CAD and/or MI, by detecting particular alleles at genetic markers that appear more frequently in individuals diagnosed with CAD and MI or individuals who are susceptible to CAD and MI. In a particular embodiment, the invention is a method of diagnosing a susceptibility to CAD and/or MI by detecting at least one allele of at least one polymorphic marker (e.g., the markers described herein). The present invention describes methods whereby detection of particular alleles of particular markers or haplotypes is indicative of a susceptibility to CAD and MI. Such prognostic or predictive assays can also be used to determine prophylactic treatment of a subject prior to the onset of symptoms of cardiovascular disease, including coronary artery disease and myocardial infarction. The present invention pertains in some embodiments to methods of clinical applications of diagnosis, e.g., diagnosis performed by a medical professional. In other embodiments, the invention pertains to methods of diagnosis or determination of a susceptibility performed by a layman. The layman can be the customer of a genotyping service. The layman may also be a genotype service provider, who performs genotype analysis on a DNA sample from an individual, in order to provide service related to genetic risk factors for particular traits or diseases, based on the genotype status of the individual (i.e., the customer). A third party who provides service to individuals can be one who provides a guidance or teaching as to how to relate or interpret genotype information to calculate or estimate genetic risk. In one embodiment, the third party may receive a sample containing genomic DNA from a customer, send the sample, or DNA isolated from the sample, to a genotype service provider, and present the customer with the genotype data and/or an interpretation of the genotype data, such as by calculating disease risk for specific markers. The customer may access his/her genotype information, including results of any risk calculations, via a secure we interface. Alternatively, the customer may receive disease risk information by other means, such as by regular mail. Recent technological advances in genotyping technologies, including high-throughput genotyping of SNP markers, such as Molecular Inversion Probe array technology (e.g., Affymetrix GeneChip), and BeadArray Technologies (e.g., Illumina GoldenGate and Infinium assays) have made it possible for individuals to have their own genome assessed for up to one million SNPs simultaneously, at relatively little cost. The resulting genotype information, made available to the individual can be compared to information from the public literature about disease or trait risk associated with various SNPs. The diagnostic application of disease-associated alleles as described herein, can thus for example be performed by the individual, through analysis of his/her genotype data, by a health professional based on results of a clinical test, or by a third party. In other words, the diagnosis or determination of a susceptibility of genetic risk can be made by health professionals, genetic counselors, third parties providing such service or by the layman, based on information about the genotype status of an individual and knowledge about the risk conferred by particular genetic risk factors (e.g., particular SNPs). In the present context, the term “diagnosing”, “diagnose a susceptibility” and “determine a susceptibility” is meant to refer to any available diagnostic method, including those mentioned above.

In certain embodiments, a sample containing genomic DNA from an individual is collected. Such sample can for example be a buccal swab, a saliva sample, a blood sample, or other suitable samples containing genomic DNA, as described further herein. The genomic DNA is then analyzed using any common technique available to the skilled person, such as high-throughput array technologies. Results from such genotyping are stored in a convenient data storage unit, such as a data carrier, including computer databases, data storage disks, or by other convenient data storage means. In certain embodiments, the computer database is an object database, a relational database or a post-relational database. The genotype data is subsequently analyzed for the presence of certain variants known to be susceptibility variants for a particular human conditions, such as the genetic variants described herein. Genotype data can be retrieved from the data storage unit using any convenient data query method. Calculating risk conferred by a particular genotype for the individual is based on comparing the genotype to previously determined risk (expressed as a relative risk (RR) or and odds ratio (OR), for example) for the genotype, for example for an heterozygous carrier of an at-risk variant for a particular disease or trait (such as CAD and/or MI). Risk presented can be the relative risk for a person, or a specific genotype of a person, compared to the population with matched gender and ethnicity. The average population risk can be expressed as a weighted average of the risks of different genotypes, using results from a reference population, and the appropriate calculations to calculate the risk of a genotype group relative to the population can then be performed. Alternatively, the risk for an individual is based on a comparison of particular genotypes, for example heterozygous carriers of an at-risk allele of a marker compared with non-carriers of the at-risk allele. Using the population average may in certain embodiments be more convenient, since it provides a measure which is easy to interpret for the user, i.e. a measure that gives the risk for the individual, based on his/her genotype, compared with the average in the population.

Overall risk for multiple risk variants can be performed using standard methodology. For example, assuming a multiplicative model, i.e. assuming that the risk of individual risk variants multiply to establish the overall effect, allows for a straight-forward calculation of the overall risk for multiple markers.

In addition, in certain other embodiments, the present invention pertains to methods of diagnosing, or aiding in the diagnosis of, a decreased susceptibility to cardiovascular disease, in particular CAD and/or MI, by detecting particular genetic marker alleles or haplotypes that appear less frequently in individuals diagnosed with CAD and/or MI than in individual not diagnosed with these diseases, or in the general population.

As described and exemplified herein, particular marker alleles or haplotypes (e.g. the markers as set forth in Table 4 and markers in linkage disequilibrium therewith) are associated with risk of coronary artery disease and/or myocardial infarction. In one embodiment, the marker allele or haplotype is one that confers a significant risk or susceptibility to coronary artery disease and/or myocardial infarction. In another embodiment, the invention relates to a method of diagnosing a susceptibility to CAD and/or MI in a human individual, the method comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual, wherein the at least one polymorphic marker is selected from the group consisting of the polymorphic markers listed in Table 4, and markers in linkage disequilibrium therewith. In another embodiment, the invention pertains to methods of diagnosing a susceptibility to CAD and/or MI in a human individual, by screening for at least one marker allele or haplotype as listed in Table 4 or markers in linkage disequilibrium therewith. In another embodiment, the marker allele or haplotype is more frequently present in a subject having, or who is susceptible to, CAD and/or MI (affected), as compared to the frequency of its presence in a healthy subject (control, such as population controls). In certain embodiments, the significance of association of the at least one marker allele or haplotype is characterized by a p value <0.05. In other embodiments, the significance of association is characterized by smaller p-values, such as <0.01, <0.001, <0.0001, <0.00001, <0.000001, <0.0000001, <0.00000001 or <0.000000001.

In these embodiments, the presence of the at least one marker allele or haplotype is indicative of a susceptibility to coronary artery disease and/or myocardial infarction. These diagnostic methods involve detecting the presence or absence of at least one marker allele or haplotype that is associated with coronary artery disease and/or myocardial infarction. The haplotypes described herein include combinations of alleles at various genetic markers (e.g., SNPs, microsatellites). The detection of the particular genetic marker alleles that make up the particular haplotypes can be performed by a variety of methods described herein and/or known in the art. For example, genetic markers can be detected at the nucleic acid level (e.g., by direct nucleotide sequencing or by other means known to the skilled in the art) or at the amino acid level if the genetic marker affects the coding sequence of a protein encoded by a coronary artery disease and/or myocardial infarction-associated nucleic acid (e.g., by protein sequencing or by immunoassays using antibodies that recognize such a protein). The marker alleles or haplotypes of the present invention correspond to fragments of a genomic DNA sequence associated with coronary artery disease and/or myocardial infarction. Such fragments encompass the DNA sequence of the polymorphic marker or haplotype in question, but may also include DNA segments in strong LD (linkage disequilibrium) with the marker or haplotype.

In one embodiment, diagnosis of a susceptibility to CAD and/or MI can be accomplished using hybridization methods, including, but not limited to, hybridization to a microarray, Southern analysis, Northern analysis, and/or in situ hybridizations (see Current Protocols in Molecular Biology, Ausubel, F. et al., eds., John Wiley & Sons, including all supplements). The presence of a specific marker allele can be indicated by sequence-specific hybridization of a nucleic acid probe specific for the particular allele. The presence of more than one specific marker allele or a specific haplotype can be indicated by using several sequence-specific nucleic acid probes, each being specific for a particular allele. In one embodiment, a haplotype can be indicated by a single nucleic acid probe that is specific for the specific haplotype (i.e., hybridizes specifically to a DNA strand comprising the specific marker alleles characteristic of the haplotype). A sequence-specific probe can be directed to hybridize to genomic DNA, RNA, or cDNA. A “nucleic acid probe”, as used herein, can be a DNA probe or an RNA probe that hybridizes to a complementary sequence. One of skill in the art would know how to design such a probe so that sequence specific hybridization will occur only if a particular allele is present in a genomic sequence from a test sample. Other methods of using hybridization probes in allele-specific detection methods include methods of single base extension of nucleotide probes flanking a single base polymorphic sites. Such methods are well known to the skilled artisan.

To determine a susceptibility or diagnose a susceptibility, a hybridization sample is formed by contacting the test sample containing an nucleic acid associated with CAD and/or MI, such as a genomic DNA sample, with at least one nucleic acid probe. A non-limiting example of a probe for detecting mRNA or genomic DNA is a labeled nucleic acid probe that is capable of hybridizing to mRNA or genomic DNA sequences described herein. The nucleic acid probe can be, for example, a full-length nucleic acid molecule, or a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length that is sufficient to specifically hybridize under stringent conditions to appropriate mRNA or genomic DNA. For example, the nucleic acid probe can comprise all or a portion of the nucleotide sequence of any one of SEQ ID NO:1-172, as set forth herein, or the probe can be the complementary sequence of such a sequence. Other suitable probes for use in the diagnostic assays of the invention are described herein. Hybridization can be performed by methods well known to the person skilled in the art (see, e.g., Current Protocols in Molecular Biology, Ausubel, F. et al., eds., John Wiley & Sons, including all supplements). In one embodiment, hybridization refers to specific hybridization, i.e., hybridization with no mismatches (exact hybridization). In one embodiment, the hybridization conditions for specific hybridization are high stringency.

Specific hybridization, if present, is detected using standard methods. If specific hybridization occurs between the nucleic acid probe and the nucleic acid in the test sample, then the sample contains the allele that is complementary to the nucleotide that is present in the nucleic acid probe. The process can be repeated for any markers of the present invention, or markers that make up a haplotype of the present invention, or multiple probes can be used concurrently to detect more than one marker alleles at a time. It is also possible to design a single probe containing more than one marker alleles of a particular haplotype (e.g., a probe containing alleles complementary to 2, 3, 4, 5 or all of the markers that make up a particular haplotype). Detection of the particular markers of the haplotype in the sample is indicative that the source of the sample has the particular haplotype (e.g., a haplotype) and therefore is susceptible to CAD and/or MI.

In one preferred embodiment, a method utilizing a detection oligonucleotide probe comprising a fluorescent moiety or group at its 3′ terminus and a quencher at its 5′ terminus, and an enhancer oligonucleotide, is employed, as described by Kutyavin et al. (Nucleic Acid Res. 34:e128 (2006)). The fluorescent moiety can be Gig Harbor Green or Yakima Yellow, or other suitable fluorescent moieties. The detection probe is designed to hybridize to a short nucleotide sequence that includes the SNP polymorphism to be detected. Preferably, the SNP is anywhere from the terminal residue to −6 residues from the 3′ end of the detection probe. The enhancer is a short oligonucleotide probe which hybridizes to the DNA template 3′ relative to the detection probe. The probes are designed such that a single nucleotide gap exists between the detection probe and the enhancer nucleotide probe when both are bound to the template. The gap creates a synthetic abasic site that is recognized by an endonuclease, such as Endonuclease IV. The enzyme cleaves the dye off the fully complementary detection probe, but cannot cleave a detection probe containing a mismatch. Thus, by measuring the fluorescence of the released fluorescent moiety, assessment of the presence of a particular allele defined by nucleotide sequence of the detection probe can be performed.

The detection probe can be of any suitable size, although preferably the probe is relatively short. In one embodiment, the probe is from 5-100 nucleotides in length. In another embodiment, the probe is from 10-50 nucleotides in length, and in another embodiment, the probe is from 12-30 nucleotides in length. Other lengths of the probe are possible and within scope of the skill of the average person skilled in the art.

In a preferred embodiment, the DNA template containing the SNP polymorphism is amplified by Polymerase Chain Reaction (PCR) prior to detection. In such an embodiment, the amplified DNA serves as the template for the detection probe and the enhancer probe.

Certain embodiments of the detection probe, the enhancer probe, and/or the primers used for amplification of the template by PCR include the use of modified bases, including modified A and modified G. The use of modified bases can be useful for adjusting the melting temperature of the nucleotide molecule (probe and/or primer) to the template DNA, for example for increasing the melting temperature in regions containing a low percentage of G or C bases, in which modified A with the capability of forming three hydrogen bonds to its complementary T can be used, or for decreasing the melting temperature in regions containing a high percentage of G or C bases, for example by using modified G bases that form only two hydrogen bonds to their complementary C base in a double stranded DNA molecule. In a preferred embodiment, modified bases are used in the design of the detection nucleotide probe. Any modified base known to the skilled person can be selected in these methods, and the selection of suitable bases is well within the scope of the skilled person based on the teachings herein and known bases available from commercial sources as known to the skilled person.

In another hybridization method, Northern analysis (see Current Protocols in Molecular Biology, Ausubel, F. et al., eds., John Wiley & Sons, supra) is used to identify the presence of a polymorphism associated with CAD and/or MI. For Northern analysis, a test sample of RNA is obtained from the subject by appropriate means. As described herein, specific hybridization of a nucleic acid probe to RNA from the subject is indicative of a particular allele complementary to the probe. For representative examples of use of nucleic acid probes, see, for example, U.S. Pat. Nos. 5,288,611 and 4,851,330.

Additionally, or alternatively, a peptide nucleic acid (PNA) probe can be used in addition to, or instead of, a nucleic acid probe in the hybridization methods described herein. A PNA is a DNA mimic having a peptide-like, inorganic backbone, such as N-(2-aminoethyl)glycine units, with an organic base (A, G, C, T or U) attached to the glycine nitrogen via a methylene carbonyl linker (see, for example, Nielsen, P., et al., Bioconjug. Chem. 5:3-7 (1994)). The PNA probe can be designed to specifically hybridize to a molecule in a sample suspected of containing one or more of the marker alleles or haplotypes that are associated with CAD and/or MI. Hybridization of the PNA probe is thus diagnostic for a susceptibility of CAD and/or MI.

In one embodiment of the invention, a test sample containing genomic DNA obtained from the subject is collected and the polymerase chain reaction (PCR) is used to amplify a fragment comprising one or more markers or haplotypes of the present invention. As described herein, identification of a particular marker allele or haplotype associated with CAD and/MI, can be accomplished using a variety of methods (e.g., sequence analysis, analysis by restriction digestion, specific hybridization, single stranded conformation polymorphism assays (SSCP), electrophoretic analysis, etc.). In another embodiment, diagnosis is accomplished by expression analysis using quantitative PCR (kinetic thermal cycling). This technique can, for example, utilize commercially available technologies, such as TaqMan® (Applied Biosystems, Foster City, Calif.). The technique can assess the presence of an alteration in the expression or composition of a polypeptide or splicing variant(s) that is encoded by a nucleic acid associated with CAD and/or MI, as described herein. Further, the expression of the variant(s) can be quantified as physically or functionally different.

In another embodiment of the methods of the invention, analysis by restriction digestion can be used to detect a particular allele if the allele results in the creation or elimination of a restriction site relative to a reference sequence. Restriction fragment length polymorphism (RFLP) analysis can be conducted, e.g., as described in Current Protocols in Molecular Biology, supra. The digestion pattern of the relevant DNA fragment indicates the presence or absence of the particular allele in the sample.

Sequence analysis can also be used to detect specific alleles or haplotypes associated with CAD and/or MI (e.g. the polymorphic markers of Table 4 and markers in linkage disequilibrium therewith). Therefore, in one embodiment, determination of the presence or absence of a particular marker alleles or haplotypes comprises sequence analysis of a test sample of DNA or RNA obtained from a subject or individual. PCR or other appropriate methods can be used to amplify a portion of a nucleic acid template, and the presence of a specific allele can then be detected directly by sequencing the polymorphic site (or multiple polymorphic sites in a haplotype) of the genomic DNA in the sample.

In another embodiment, arrays of oligonucleotide probes that are complementary to target nucleic acid sequence segments from a subject, can be used to identify polymorphisms in a nucleic acid associated with CAD and/or MI (e.g. the polymorphic markers of Table 4 and markers in linkage disequilibrium therewith). For example, an oligonucleotide array can be used. Oligonucleotide arrays typically comprise a plurality of different oligonucleotide probes that are coupled to a surface of a substrate in different known locations. These arrays can generally be produced using mechanical synthesis methods or light directed synthesis methods that incorporate a combination of photolithographic methods and solid phase oligonucleotide synthesis methods, or by other methods known to the person skilled in the art (see, e.g., Fodor, S. et al., Science, 251:767-773 (1991); Pirrung et al., U.S. Pat. No. 5,143,854 (see also published PCT Application No. WO 90/15070); and Fodor. S. et al., published PCT Application No. WO 92/10092 and U.S. Pat. No. 5,424,186, the entire teachings of each of which are incorporated by reference herein). Techniques for the synthesis of these arrays using mechanical synthesis methods are described in, e.g., U.S. Pat. No. 5,384,261; the entire teachings of which are incorporated by reference herein. In another example, linear arrays can be utilized. Additional descriptions of use of oligonucleotide arrays for detection of polymorphisms can be found, for example, in U.S. Pat. Nos. 5,858,659 and 5,837,832, the entire teachings of both of which are incorporated by reference herein.

Other methods of nucleic acid analysis that are available to those skilled in the art can be used to detect a particular allele at a polymorphic site associated with CAD and/or MI (e.g. the polymorphic markers of Table 4 and markers in linkage disequilibrium therewith). Representative methods include, for example, direct manual sequencing (Church and Gilbert, Proc. Natl. Acad. Sci. USA, 81: 1991-1995 (1988); Sanger, F., et al., Proc. Natl. Acad. Sci. USA, 74:5463-5467 (1977); Beavis, et al., U.S. Pat. No. 5,288,644); automated fluorescent sequencing; single-stranded conformation polymorphism assays (SSCP); clamped denaturing gel electrophoresis (CDGE); denaturing gradient gel electrophoresis (DGGE) (Sheffield, V., et al., Proc. Natl. Acad. Sci. USA, 86:232-236 (1989)), mobility shift analysis (Orita, M., et al., Proc. Natl. Acad. Sci. USA, 86:2766-2770 (1989)), restriction enzyme analysis (Flavell, R., et al., Cell, 15:25-41 (1978); Geever, R., et al., Proc. Natl. Acad. Sci. USA, 78:5081-5085 (1981)); heteroduplex analysis; chemical mismatch cleavage (CMC) (Cotton, R., et al., Proc. Natl. Acad. Sci. USA, 85:4397-4401 (1985)); RNase protection assays (Myers, R., et al., Science, 230:1242-1246 (1985); use of polypeptides that recognize nucleotide mismatches, such as E. coli mutS protein; and allele-specific PCR.

In another embodiment of the invention, diagnosis of CAD and/or MI or a susceptibility to CAD and/or MI can be made by examining expression and/or composition of a polypeptide encoded by a nucleic acid associated with these diseases, in those instances where the genetic marker(s) or haplotype(s) of the present invention result in a change in the composition or expression of the polypeptide. Thus, diagnosis or determination of a susceptibility can be made by examining expression and/or composition of one of these polypeptides, or another polypeptide encoded by a nucleic acid associated with CAD and/or MI, in those instances where the genetic marker or haplotype of the present invention results in a change in the composition or expression of the polypeptide. The haplotypes and markers of the present invention that show association to CAD and MI may play a role through their effect on one or more of these nearby genes (e.g., the Lp(a) gene). Possible mechanisms affecting these genes include, e.g., effects on transcription, effects on RNA splicing, alterations in relative amounts of alternative splice forms of mRNA, effects on RNA stability, effects on transport from the nucleus to cytoplasm, and effects on the efficiency and accuracy of translation.

Thus, in another embodiment, the variants (markers or haplotypes) of the invention showing association to CAD and/or MI affect the expression of a nearby gene, such as the Lp(a) gene. It is well known that regulatory element affecting gene expression may be located far away, even as far as tenths or hundreds of kilobases away, from the promoter region of a gene. By assaying for the presence or absence of at least one allele of at least one polymorphic marker of the present invention, it is thus possible to assess the expression level of such nearby genes. It is thus contemplated that the detection of the markers or haplotypes of the present invention can be used for assessing expression of genes associated with (in LD with) the associated markers.

A variety of methods can be used for detecting protein expression levels, including enzyme linked immunosorbent assays (ELISA), Western blots, immunoprecipitations and immunofluorescence. A test sample from a subject is assessed for the presence of an alteration in the expression and/or an alteration in composition of the polypeptide encoded by a nucleic acid associated with CAD and/or MI. An alteration in expression of a polypeptide encoded by a nucleic acid associated with CAD and/or MI can be, for example, an alteration in the quantitative polypeptide expression (i.e., the amount of polypeptide produced). An alteration in the composition of a polypeptide encoded by a nucleic acid associated with CAD and/or MI is an alteration in the qualitative polypeptide expression (e.g., expression of a mutant polypeptide or of a different splicing variant). In one embodiment, diagnosis of a susceptibility to CAD and/or MI is made by detecting a particular splicing variant encoded by a nucleic acid associated with these diseases, or a particular pattern of splicing variants.

Both such alterations (quantitative and qualitative) can also be present. An “alteration” in the polypeptide expression or composition, as used herein, refers to an alteration in expression or composition in a test sample, as compared to the expression or composition of the polypeptide in a control sample. A control sample is a sample that corresponds to the test sample (e.g., is from the same type of cells), and is from a subject who is not affected by, and/or who does not have a susceptibility to, CAD and/or MI. In one embodiment, the control sample is from a subject that does not possess a marker allele or haplotype associated with CAD and/or MI, as described herein. Similarly, the presence of one or more different splicing variants in the test sample, or the presence of significantly different amounts of different splicing variants in the test sample, as compared with the control sample, can be indicative of a susceptibility to CAD and/or MI. An alteration in the expression or composition of the polypeptide in the test sample, as compared with the control sample, can be indicative of a specific allele in the instance where the allele alters a splice site relative to the reference in the control sample. Various means of examining expression or composition of a polypeptide encoded by a nucleic acid are known to the person skilled in the art and can be used, including spectroscopy, colorimetry, electrophoresis, isoelectric focusing, and immunoassays (e.g., David et al., U.S. Pat. No. 4,376,110) such as immunoblotting (see, e.g., Current Protocols in Molecular Biology, particularly chapter 10, supra).

For example, in one embodiment, an antibody (e.g., an antibody with a detectable label) that is capable of binding to a polypeptide encoded by a nucleic acid associated with CAD and/or MI can be used. Antibodies can be polyclonal or monoclonal. An intact antibody, or a fragment thereof (e.g., Fv, Fab, Fab′, F(ab′)₂) can be used. The term “labeled”, with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a labeled secondary antibody (e.g., a fluorescently-labeled secondary antibody) and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin.

In one embodiment of this method, the level or amount of polypeptide encoded by a nucleic acid associated with CAD and/or MI in a test sample is compared with the level or amount of the polypeptide in a control sample. A level or amount of the polypeptide in the test sample that is higher or lower than the level or amount of the polypeptide in the control sample, such that the difference is statistically significant, is indicative of an alteration in the expression of the polypeptide encoded by the nucleic acid, and is diagnostic for a particular allele or haplotype responsible for causing the difference in expression. Alternatively, the composition of the polypeptide in a test sample is compared with the composition of the polypeptide in a control sample. In another embodiment, both the level or amount and the composition of the polypeptide can be assessed in the test sample and in the control sample.

In another embodiment, the diagnosis of a susceptibility to CAD and/or MI is made by detecting at least one marker or haplotypes of the present invention (e.g., associated alleles of the markers listed in Table 4, and markers in linkage disequilibrium therewith), in combination with an additional protein-based, RNA-based or DNA-based assay.

Kits

Kits useful in the methods of the invention comprise components useful in any of the methods described herein, including for example, primers for nucleic acid amplification, hybridization probes, restriction enzymes (e.g., for RFLP analysis), allele-specific oligonucleotides, antibodies that bind to an altered polypeptide encoded by a nucleic acid of the invention as described herein (e.g., a genomic segment comprising at least one polymorphic marker and/or haplotype of the present invention) or to a non-altered (native) polypeptide encoded by a nucleic acid of the invention as described herein, means for amplification of a nucleic acid templates, means for analyzing the nucleic acid sequence of a nucleic acids, means for analyzing the amino acid sequence of a polypeptide encoded by a nucleic acid associated with CAD and/or MI, etc. The kits can for example include necessary buffers, nucleic acid primers for amplifying nucleic acids of the invention (e.g., a nucleic acid segment comprising one or more of the polymorphic markers as described herein), and reagents for allele-specific detection of the fragments amplified using such primers and necessary enzymes (e.g., DNA polymerase). Additionally, kits can provide reagents for assays to be used in combination with the methods of the present invention, e.g., reagents for use with other diagnostic assays for CAD and/or MI.

In one embodiment, the invention is a kit for assaying a sample from a subject to detect a susceptibility to coronary artery disease and/or myocardial infarction in a subject, wherein the kit comprises reagents necessary for selectively detecting at least one allele of at least one polymorphism of the present invention in the genome of the individual. In a particular embodiment, the reagents comprise at least one contiguous oligonucleotide that hybridizes to a fragment of the genome of the individual comprising at least one polymorphism of the present invention. In another embodiment, the reagents comprise at least one pair of oligonucleotides that hybridize to opposite strands of a genomic segment obtained from a subject, wherein each oligonucleotide primer pair is designed to selectively amplify a fragment of the genome of the individual that includes one polymorphism, wherein the polymorphism is selected from the group consisting of the polymorphisms as defined in and polymorphic markers in linkage disequilibrium therewith. In yet another embodiment the fragment is at least 20 base pairs in size. Such oligonucleotides or nucleic acids (e.g., oligonucleotide primers) can be designed using portions of the nucleic acids flanking polymorphisms (e.g., SNPs or microsatellites) that are indicative of coronary artery disease and myocardial infarction. In another embodiment, the kit comprises one or more labeled nucleic acids capable of detecting one or more specific polymorphic markers or haplotypes associated with coronary artery disease and/or myocardial infarction, and reagents for detection of the label. Suitable labels include, e.g., a radioisotope, a fluorescent label, an enzyme label, an enzyme co-factor label, a magnetic label, a spin label, an epitope label.

In particular embodiments, the polymorphic marker or haplotype to be detected by the reagents of the kit comprises one or more markers, two or more markers, three or more markers, four or more markers or five or more markers selected from the group consisting of the markers in Table 3. In another embodiment, the marker or haplotype to be detected comprises the markers listed in Table 4, and markers in linkage disequilibrium therewith. In another embodiment, the marker or haplotype to be detected is selected from marker rs11751605, rs6076623, rs1412444, rs2163612, rs1029396, rs2243547, rs12534186, rs12134779 and rs7158073. In another embodiment, the marker or haplotype to be detected is selected from marker rs11751605, rs6076623, rs1412444, rs2163612 and rs1029396. In another embodiment, the marker or haplotype to be detected is marker rs11751605. In such embodiments, the presence of the marker or haplotype is indicative of a susceptibility (increased susceptibility or decreased susceptibility) to cardiovascular disease, including coronary artery disease and myocardial infarction.

In one preferred embodiment, the kit for detecting the markers of the invention comprises a detection oligonucleotide probe, that hybridizes to a segment of template DNA containing a SNP polymorphisms to be detected, an enhancer oligonucleotide probe and an endonuclease. As explained in the above, the detection oligonucleotide probe comprises a fluorescent moiety or group at its 3′ terminus and a quencher at its 5′ terminus, and an enhancer oligonucleotide, is employed, as described by Kutyavin et al. (Nucleic Acid Res. 34:e128 (2006)). The fluorescent moiety can be Gig Harbor Green or Yakima Yellow, or other suitable fluorescent moieties. The detection probe is designed to hybridize to a short nucleotide sequence that includes the SNP polymorphism to be detected. Preferably, the SNP is anywhere from the terminal residue to −6 residues from the 3′ end of the detection probe. The enhancer is a short oligonucleotide probe which hybridizes to the DNA template 3′ relative to the detection probe. The probes are designed such that a single nucleotide gap exists between the detection probe and the enhancer nucleotide probe when both are bound to the template. The gap creates a synthetic abasic site that is recognized by an endonuclease, such as Endonuclease IV. The enzyme cleaves the dye off the fully complementary detection probe, but cannot cleave a detection probe containing a mismatch. Thus, by measuring the fluorescence of the released fluorescent moiety, assessment of the presence of a particular allele defined by nucleotide sequence of the detection probe can be performed.

The detection probe can be of any suitable size, although preferably the probe is relatively short. In one embodiment, the probe is from 5-100 nucleotides in length. In another embodiment, the probe is from 10-50 nucleotides in length, and in another embodiment, the probe is from 12-30 nucleotides in length. Other lengths of the probe are possible and within scope of the skill of the average person skilled in the art.

In a preferred embodiment, the DNA template containing the SNP polymorphism is amplified by Polymerase Chain Reaction (PCR) prior to detection, and primers for such amplification are included in the reagent kit. In such an embodiment, the amplified DNA serves as the template for the detection probe and the enhancer probe.

In one embodiment, the DNA template is amplified by means of Whole Genome Amplification (WGA) methods, prior to assessment for the presence of specific polymorphic markers as described herein. Standard methods well known to the skilled person for performing WGA may be utilized, and are within scope of the invention. In one such embodiment, reagents for performing WGA are included in the reagent kit.

Certain embodiments of the detection probe, the enhancer probe, and/or the primers used for amplification of the template by PCR include the use of modified bases, including modified A and modified G. The use of modified bases can be useful for adjusting the melting temperature of the nucleotide molecule (probe and/or primer) to the template DNA, for example for increasing the melting temperature in regions containing a low percentage of G or C bases, in which modified A with the capability of forming three hydrogen bonds to its complementary T can be used, or for decreasing the melting temperature in regions containing a high percentage of G or C bases, for example by using modified G bases that form only two hydrogen bonds to their complementary C base in a double stranded DNA molecule. In a preferred embodiment, modified bases are used in the design of the detection nucleotide probe. Any modified base known to the skilled person can be selected in these methods, and the selection of suitable bases is well within the scope of the skilled person based on the teachings herein and known bases available from commercial sources as known to the skilled person.

In one of such embodiments, the presence of the marker or haplotype is indicative of a susceptibility (increased susceptibility or decreased susceptibility) to CAD and/or MI. In another embodiment, the presence of the marker or haplotype is indicative of response to a therapeutic agent for a cardiovascular disease, such as CAD and MI. In another embodiment, the presence of the marker or haplotype is indicative of prognosis of MI and/or CAD. In yet another embodiment, the presence of the marker or haplotype is indicative of progress of treatment of CAD and/or MI. Such treatment may include intervention by surgery, medication or by other means (e.g., lifestyle changes).

In a further aspect of the present invention, a pharmaceutical pack (kit) is provided, the pack comprising a therapeutic agent and a set of instructions for administration of the therapeutic agent to humans diagnostically tested for one or more variants of the present invention, as disclosed herein. The therapeutic agent can be a small molecule drug, an antibody, a peptide, an antisense or RNAi molecule, or other therapeutic molecules. In one embodiment, an individual identified as a carrier of at least one variant of the present invention is instructed to take a prescribed dose of the therapeutic agent. In one such embodiment, an individual identified as a homozygous carrier of at least one variant of the present invention is instructed to take a prescribed dose of the therapeutic agent. In another embodiment, an individual identified as a non-carrier of at least one variant of the present invention is instructed to take a prescribed dose of the therapeutic agent.

In certain embodiments, the kit further comprises a set of instructions for using the reagents comprising the kit.

Therapeutic Agents

Variants of the present invention (e.g., the markers and/or haplotypes of the invention as described herein, e.g., the markers listed in Table 3 and 4) can be used to identify novel therapeutic targets for coronary artery disease or myocardial infarction, or other cardiovascular disease. For example, genes containing, or in linkage disequilibrium with, variants (markers and/or haplotypes) associated with cardiovascular disease, or their products (e.g., Lipoprotein(a) gene and its gene product), as well as genes or their products that are directly or indirectly regulated by or interact with these genes or their products, can be targeted for the development of therapeutic agents to treat cardiovascular disease, or prevent or delay onset of symptoms associated with cardiovascular disease. Therapeutic agents may comprise one or more of, for example, small non-protein and non-nucleic acid molecules, proteins, peptides, protein fragments, nucleic acids (DNA, RNA), PNA (peptide nucleic acids), or their derivatives or mimetics which can modulate the function and/or levels of the target genes or their gene products.

The nucleic acids and/or variants of the invention, or nucleic acids comprising their complementary sequence, may be used as antisense constructs to control gene expression in cells, tissues or organs. The methodology associated with antisense techniques is well known to the skilled artisan, and is described and reviewed in AntisenseDrug Technology: Principles, Strategies, and Applications, Crooke, ed., Marcel Dekker Inc., New York (2001). In general, antisense nucleic acid molecules are designed to be complementary to a region of mRNA expressed by a gene, so that the antisense molecule hybridizes to the mRNA, thus blocking translation of the mRNA into protein. Several classes of antisense oligonucleotide are known to those skilled in the art, including cleavers and blockers. The former bind to target RNA sites, activate intracellular nucleases (e.g., RnaseH or Rnase L), that cleave the target RNA. Blockers bind to target RNA, inhibit protein translation by steric hindrance of the ribosomes. Examples of blockers include nucleic acids, morpholino compounds, locked nucleic acids and methylphosphonates (Thompson, Drug Discovery Today, 7:912-917 (2002)). Antisense oligonucleotides are useful directly as therapeutic agents, and are also useful for determining and validating gene function, for example by gene knock-out or gene knock-down experiments. Antisense technology is further described in Lavery et al., Curr. Opin. Drug Discov. Devel. 6:561-569 (2003), Stephens et al., Curr. Opin. Mol. Ther. 5:118-122 (2003), Kurreck, Eur. J. Biochem. 270:1628-44 (2003), Dias et al., Mol. Cancer Ter. 1:347-55 (2002), Chen, Methods Mol. Med. 75:621-636 (2003), Wang et al., Curr. Cancer Drug Targets 1:177-96 (2001), and Bennett, Antisense Nucleic Acid Drug. Dev. 12:215-24 (2002)

The variants described herein can be used for the selection and design of antisense reagents that are specific for particular variants. Using information about the variants described herein, antisense oligonucleotides or other antisense molecules that specifically target mRNA molecules that contain one or more variants of the invention can be designed. In this manner, expression of mRNA molecules that contain one or more variant of the present invention (markers and/or haplotypes) can be inhibited or blocked. In one embodiment, the antisense molecules are designed to specifically bind a particular allelic form (i.e., one or several variants (alleles and/or haplotypes)) of the target nucleic acid, thereby inhibiting translation of a product originating from this specific allele or haplotype, but which do not bind other or alternate variants at the specific polymorphic sites of the target nucleic acid molecule.

As antisense molecules can be used to inactivate mRNA so as to inhibit gene expression, and thus protein expression, the molecules can be used to treat a disease or disorder, such as a cardiovascular disease. The methodology can involve cleavage by means of ribozymes containing nucleotide sequences complementary to one or more regions in the mRNA that attenuate the ability of the mRNA to be translated. Such mRNA regions include, for example, protein-coding regions, in particular protein-coding regions corresponding to catalytic activity, substrate and/or ligand binding sites, or other functional domains of a protein.

The phenomenon of RNA interference (RNAi) has been actively studied for the last decade, since its original discovery in C. elegans (Fire et al., Nature 391:806-11 (1998)), and in recent years its potential use in treatment of human disease has been actively pursued (reviewed in Kim & Rossi, Nature Rev. Genet. 8:173-204 (2007)). RNA interference (RNAi), also called gene silencing, is based on using double-stranded RNA molecules (dsRNA) to turn off specific genes. In the cell, cytoplasmic double-stranded RNA molecules (dsRNA) are processed by cellular complexes into small interfering RNA (siRNA). The siRNA guide the targeting of a protein-RNA complex to specific sites on a target mRNA, leading to cleavage of the mRNA (Thompson, Drug Discovery Today, 7:912-917 (2002)). The siRNA molecules are typically about 20, 21, 22 or 23 nucleotides in length. Thus, one aspect of the invention relates to isolated nucleic acid molecules, and the use of those molecules for RNA interference, i.e. as small interfering RNA molecules (siRNA). In one embodiment, the isolated nucleic acid molecules are 18-26 nucleotides in length, preferably 19-25 nucleotides in length, more preferably 20-24 nucleotides in length, and more preferably 21, 22 or 23 nucleotides in length.

Another pathway for RNAi-mediated gene silencing originates in endogenously encoded primary microRNA (pri-miRNA) transcripts, which are processed in the cell to generate precursor miRNA (pre-miRNA). These miRNA molecules are exported from the nucleus to the cytoplasm, where they undergo processing to generate mature miRNA molecules (miRNA), which direct translational inhibition by recognizing target sites in the 3′ untranslated regions of mRNAs, and subsequent mRNA degradation by processing P-bodies (reviewed in Kim & Rossi, Nature Rev. Genet. 8:173-204 (2007)).

Clinical applications of RNAi include the incorporation of synthetic siRNA duplexes, which preferably are approximately 20-23 nucleotides in size, and preferably have 3′ overlaps of 2 nucleotides. Knockdown of gene expression is established by sequence-specific design for the target mRNA. Several commercial sites for optimal design and synthesis of such molecules are known to those skilled in the art.

Other applications provide longer siRNA molecules (typically 25-30 nucleotides in length, preferably about 27 nucleotides), as well as small hairpin RNAs (shRNAs; typically about 29 nucleotides in length). The latter are naturally expressed, as described in Amarzguioui et al. (FEBS Lett. 579:5974-81 (2005)). Chemically synthetic siRNAs and shRNAs are substrates for in vivo processing, and in some cases provide more potent gene-silencing than shorter designs (Kim et al., Nature Biotechnol. 23:222-226 (2005); Siolas et al., Nature Biotechnol. 23:227-231 (2005)). In general siRNAs provide for transient silencing of gene expression, because their intracellular concentration is diluted by subsequent cell divisions. By contrast, expressed shRNAs mediate long-term, stable knockdown of target transcripts, for as long as transcription of the shRNA takes place (Marques et al., Nature Biotechnol. 23:559-565 (2006); Brummelkamp et al., Science 296: 550-553 (2002)).

Since RNAi molecules, including siRNA, miRNA and shRNA, act in a sequence-dependent manner, the variants of the present invention (e.g., the markers and haplotypes set forth in Tables 3, 4 and 5) can be used to design RNAi reagents that recognize specific nucleic acid molecules comprising specific alleles and/or haplotypes (e.g., the alleles and/or haplotypes of the present invention), while not recognizing nucleic acid molecules comprising other alleles or haplotypes. These RNAi reagents can thus recognize and destroy the target nucleic acid molecules. As with antisense reagents, RNAi reagents can be useful as therapeutic agents (i.e., for turning off disease-associated genes or disease-associated gene variants), but may also be useful for characterizing and validating gene function (e.g., by gene knock-out or gene knock-down experiments).

Delivery of RNAi may be performed by a range of methodologies known to those skilled in the art. Methods utilizing non-viral delivery include cholesterol, stable nucleic acid-lipid particle (SNALP), heavy-chain antibody fragment (Fab), aptamers and nanoparticles. Viral delivery methods include use of lentivirus, adenovirus and adeno-associated virus. The siRNA molecules are in some embodiments chemically modified to increase their stability. This can include modifications at the 2′ position of the ribose, including 2′-O-methylpurines and 2′-fluoropyrimidines, which provide resistance to Rnase activity. Other chemical modifications are possible and known to those skilled in the art.

The following references provide a further summary of RNAi, and possibilities for targeting specific genes using RNAi: Kim & Rossi, Nat. Rev. Genet. 8:173-184 (2007), Chen & Rajewsky, Nat. Rev. Genet. 8: 93-103 (2007), Reynolds, et al., Nat. Biotechnol. 22:326-330 (2004), Chi et al., Proc. Natl. Acad. Sci. USA 100:6343-6346 (2003), Vickers et al., J. Biol. Chem. 278:7108-7118 (2003), Agami, Curr. Opin. Chem. Biol. 6:829-834 (2002), Lavery, et al., Curr. Opin. Drug Discov. Devel. 6:561-569 (2003), Shi, Trends Genet. 19:9-12 (2003), Shuey et al., Drug Discov. Today 7:1040-46 (2002), McManus et al., Nat. Rev. Genet. 3:737-747 (2002), Xia et al., Nat. Biotechnol. 20:1006-10 (2002), Plasterk et al., curr. Opin. Genet. Dev. 10:562-7 (2000), Bosher et al., Nat. Cell Biol. 2:E31-6 (2000), and Hunter, Curr. Biol. 9:R440-442 (1999).

A genetic defect leading to increased predisposition or risk for development of a cardiovascular disease, or a defect causing the disease, may be corrected permanently by administering to a subject carrying the defect a nucleic acid fragment that incorporates a repair sequence that supplies the normal/wild-type nucleotide(s) at the site of the genetic defect. Such site-specific repair sequence may concompass an RNA/DNA oligonucleotide that operates to promote endogenous repair of a subject's genomic DNA. The administration of the repair sequence may be performed by an appropriate vehicle, such as a complex with polyethelenimine, encapsulated in anionic liposomes, a viral vector such as an adenovirus vector, or other pharmaceutical compositions suitable for promoting intracellular uptake of the adminstered nucleic acid. The genetic defect may then be overcome, since the chimeric oligonucleotides induce the incorporation of the normal sequence into the genome of the subject, leading to expression of the normal/wild-type gene product. The replacement is propagated, thus rendering a permanent repair and alleviation of the symptoms associated with the disease or condition.

The present invention provides methods for identifying compounds or agents that can be used to treat cardiovascular diseases, such as coronary artery disease and myocardial infarction. Thus, the variants of the invention are useful as targets for the identification and/or development of therapeutic agents. In certain embodiments, such methods include assaying the ability of an agent or compound to modulate the activity and/or expression of a nucleic acid that includes at least one of the variants (markers and/or haplotypes) of the present invention, or the encoded product of the nucleic acid (e.g., the Lp(a) gene). This in turn can be used to identify agents or compounds that inhibit or alter the undesired activity or expression of the encoded nucleic acid product. Assays for performing such experiments can be performed in cell-based systems or in cell-free systems, as known to the skilled person. Cell-based systems include cells naturally expressing the nucleic acid molecules of interest, or recombinant cells that have been genetically modified so as to express a certain desired nucleic acid molecule.

Variant gene expression in a patient can be assessed by expression of a variant-containing nucleic acid sequence (for example, a gene containing at least one variant of the present invention, which can be transcribed into RNA containing the at least one variant, and in turn translated into protein), or by altered expression of a normal/wild-type nucleic acid sequence due to variants affecting the level or pattern of expression of the normal transcripts, for example variants in the regulatory or control region of the gene. Assays for gene expression include direct nucleic acid assays (mRNA), assays for expressed protein levels, or assays of collateral compounds involved in a pathway, for example a signal pathway. Furthermore, the expression of genes that are up- or down-regulated in response to the signal pathway can also be assayed. One embodiment includes operably linking a reporter gene, such as luciferase, to the regulatory region of the gene(s) of interest.

Modulators of gene expression can in one embodiment be identified when a cell is contacted with a candidate compound or agent, and the expression of mRNA is determined. The expression level of mRNA in the presence of the candidate compound or agent is compared to the expression level in the absence of the compound or agent. Based on this comparison, candidate compounds or agents for treating cardiovascular disease can be identified as those modulating the gene expression of the variant gene. When expression of mRNA or the encoded protein is statistically significantly greater in the presence of the candidate compound or agent than in its absence, then the candidate compound or agent is identified as a stimulator or up-regulator of expression of the nucleic acid. When nucleic acid expression or protein level is statistically significantly less in the presence of the candidate compound or agent than in its absence, then the candidate compound is identified as an inhibitor or down-regulator of the nucleic acid expression.

The invention further provides methods of treatment using a compound identified through drug (compound and/or agent) screening as a gene modulator (i.e. stimulator and/or inhibitor of gene expression).

Methods of Assessing Probability of Response to Therapeutic Agents and Methods, Methods of Monitoring Treatment Progress and Methods for Treating Cardiovascular Disease

As is known in the art, individuals can have differential responses to a particular therapy (e.g., a therapeutic agent or therapeutic method). Pharmacogenomics addresses the issue of how genetic variations (e.g., the variants (markers and/or haplotypes) of the present invention) affect drug response, due to altered drug disposition and/or abnormal or altered action of the drug. Thus, the basis of the differential response may be genetically determined in part. Clinical outcomes due to genetic variations affecting drug response may result in toxicity of the drug in certain individuals (e.g., carriers or non-carriers of the genetic variants of the present invention), or therapeutic failure of the drug. Therefore, the variants of the present invention may determine the manner in which a therapeutic agent and/or method acts on the body, or the way in which the body metabolizes the therapeutic agent.

Accordingly, in one embodiment, the presence of a particular allele of a polymorphic marker, or the presence of a haplotype as described herein is indicative of a different response rate to a particular treatment modality for coronary artery disease or myocardial infarction. This means that a patient diagnosed with coronary artery disease or myocardial infarction, or at risk for coronary artery disease or myocardial infarction, and carrying a certain allele at a polymorphic or haplotype of the present invention (e.g., the at-risk alleles and/or haplotypes of the invention) would respond better to, or worse to, a specific therapeutic, drug and/or other therapy used to treating these diseases. Therefore, the presence or absence of the marker allele or haplotype could aid in deciding what treatment is appropriate for the patient. For example, for a newly diagnosed patient, the presence of a marker or haplotype of the present invention may be assessed (e.g., through testing DNA derived from a blood sample or other sample containing genomic DNA, as described herein). If the patient is positive for a marker allele or haplotype at (that is, at least one specific allele of the marker, or haplotype, is present), then the physician recommends one particular therapy (e.g., one particular therapeutic agent or a combination of therapeutic agents), while if the patient is negative for the at least one allele of a marker, or a haplotype, then a different course of therapy may be recommended (which may include recommending that no immediate therapy, other than serial monitoring for progression of the disease, be performed). Thus, the patient's carrier status could be used to help determine whether a particular treatment modality should be administered. The value lies within the possibilities of being able to diagnose the disease at an early stage and provide information to the clinician about prognosis/aggressiveness of the disease in order to be able to apply the most appropriate treatment.

As one example, the application of a genetic test can identify subjects who are at high risk of developing restenosis after coronary stent procedure. While it is know that some treatment methods for coronary artery disease, such as introducing drug-eluting stents and brachytherapy, are associated with decreased risk of in-stent restenosis, the use of these methods are restricted because of number of reasons, including economical reasons. Identification of individuals within the group of those undergoing coronary stent procedure who are carriers of particular genetic risk variants will allow targeting of those individuals that would benefit most from therapy associated with decreased risk of in-stent restenosis.

The present invention also relates to methods of monitoring effectiveness of a treatment for coronary artery disease and/or myocardial infarction. This can be done based on the genotype and/or haplotype status of the markers and haplotypes of the present invention, or by monitoring expression of genes that are associated with the variants (markers and haplotypes) of the present invention (e.g., the Lp(a) gene). The risk gene mRNA or the encoded polypeptide can be measured in a tissue sample (e.g., a peripheral blood sample, or a biopsy sample). Expression levels and/or mRNA levels can thus be determined before and during treatment to monitor its effectiveness. Alternatively, or concomitantly, the genotype and/or haplotype status of at least one risk variant for coronary artery disease or myocardial infarction as presented herein is determined before and during treatment to monitor its effectiveness.

The treatment modules of coronary artery disease and/or myocardial infarction to which the invention pertains includes, but is not limited to, methods of treatment for coronary artery disease or myocardial infarction or a susceptibility to coronary artery disease or myocardial infarction; methods of phophylaxis therapy for coronary artery disease or myocardial infarction; methods of treatment for acute coronary syndrome (e.g., unstable angina, non-ST-elevation myocardial infarction (NSTEMI) or ST-elevation myocardial infarction (STEMI)); methods for reducing risk of coronary artery disease and/or myocardial infarction; methods for decreasing risk of a second myocardial infarction; methods of treatment for atherosclerosis, such as for patients requiring treatment (e.g., angioplasty, stents, revascularization procedure) to restore blood flow in arteries (e.g., coronary, carotid, and/or femoral arteries); and/or methods for decreasing leukotriene synthesis (e.g., for treatment of coronary artery disease or myocardial infarction).

Treatment of coronary artery disease and myocardial infarction (MI) may be categorized as (i) preventive treatment and (ii) disease management. The main goal of the latter is to minimize damage to the heart and prevent further complications. The first line of disease management typically includes one or more of administration of oxygen, aspirin, glyceryl nitrate (nitroglycerin) and analgesia, such as morphine or related drugs. Once diagnosis of MI is made, additional therapy may include beta blockers, anticoagulation agents, including heparin and/or low molecular weigh heparin, and possibly also antiplatelet agents, such as clopidogrel. Secondary prevention, i.e. the management of risk of a recurrent MI, typically includes one or more of the following: Antiplatelet drug therapy, including aspirin and/or clopidogrel, beta blocker therapy, including metoprolol and carvedilol, ACE inhibitor therapy, Statin therapy, Aldosterone antagonist therapy, including eplerenone. Further, non-therapeutic administration of food supplements such as omega-3 fatty acids may be beneficial.

New preventive therapy for coronary artery disease and/or myocardial infarction, includes agents that act on the formation and/or rupture of plaques, and also includes phosphodiesterase inhibitors. Such therapeutic agents are useful in the methods of the invention, as described herein. This includes, but is not limited to, agents that target the leukotriene synthesis pathway. The leukotriene synthesis inhibitor can be any agent that inhibits or antagonizes a member of the leukotriene synthesis pathway (e.g., FLAP, 5-LO, LTC4S, LTA4H, and LTB4DH). For example, the leukotriene synthesis inhibitor can be an agent that inhibits or antagonizes FLAP polypeptide activity (e.g., a FLAP inhibitor) and/or FLAP nucleic acid expression (e.g., a FLAP nucleic acid antagonist). In another embodiment, the leukotriene synthesis inhibitor is an agent that inhibits or antagonizes polypeptide activity and/or nucleic acid expression of another member of the leukotriene biosynthetic pathway (e.g., LTC4S, LTA4H) or that increases breakdown of leukotrienes (e.g., LTB4DH). In preferred embodiments, the agent alters activity and/or nucleic acid expression of FLAP, LTA4H or of 5-LO. Preferred agents include those set forth in the Agent Table I herein. In another embodiment, preferred agents can be: 1-((4-chlorophenyl)methyl)-3-((1,1-dimethylethyl)thio)-alpha,alpha-dimethyl-5-(2-quinolinylmethoxy)-1H-Indole-2-propanoic acid otherwise known as MK-0591, (R)-(+)-alpha-cyclopentyl-4-(2-quinolinylmethoxy)-Benzeneacetic acid, otherwise known as BAY-x-1005, 3-(3-(1,1-dimethylethylthio-5-(quinoline-2-ylmethoxy)-1-(4-chloromethylphenyl)indole-2-yl)-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid otherwise known as A-81834; or can be zileuton, atreleuton, 6-((3-fluoro-5-(tetrahydro-4-methoxy-2H-pyran-4yl)phenoxy)methyl)-1-methyl-2(1H)-quinlolinone otherwise known as ZD-2138, 1-((4-chlorophenyl)methyl)-3-((1,1-dimethylethyl)thio)-alpha,alpha-dimethyl-5-(2-quinolinylmethoxy)-1H-Indole-2-propanoic acid otherwise known as MK-886, 4-(3-(4-(2-Methyl-imidazol-1-yl)-phenylsulfanyl)-phenyl)-tetrahydro-pyran-4-carboxylic acid amide otherwise known as CJ-13610. Additional agents include those described in Penning et al., Med Chem. 2002 45(16):3482-90, Penning, Curr Pharm Des. 2001, 7(3):163-79 and Penning et al., J Med Chem. 2000 43(4):721-35. In another embodiment, the agent alters metabolism or activity of a leukotriene (e.g., LTA4, LTB4, LTC4, LTD4, LTE4, Cys LT1, Cys LT2), such as leukotriene antagonists or antibodies to leukotrienes, as well as agents which alter activity of a leukotriene receptor (e.g., BLT1, BLT2, CysLTR1, and CysLTR2).

In other preferred embodiments, the agent alters activity and/or nucleic acid expression of LTA4H. Preferred agents include those set forth in the Agent Table II; but also include the following agents: 1-[2-[4-(phenylmethyl)phenoxy]ethyl]-2-methyl-4-tetrazolylpieridine; 1-[2-[4-(4-oxazolyl)phenoxy)phenoxy]ethyl]pyrrolidine; 3-[methyl[3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propionic acid; methyl 3-[methyl[3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propionate; 3-[methyl[3-[4-(3-thienylmethyl)phenoxy]propyl]amino]propionic acid; methyl-3-[methyl[3-4-(3-thienylmethyl)phenoxy]propyl]amino]propionate; 3-[methyl[3-[4-(4-fluorophenoxy)phenoxy]propyl]amino]propionic acid; 3-[methyl[3-[4-(4-biphenyloxy)phenoxy]propyl]amino]propionic acid; N-[3-[[3-[4-(phenylmethyl)phenoxy]propyl]methylamino]propionyl]benzenesulfonamide; 1-[2-[4-(phenylmethyl)phenoxy]ethyl]-2-methyl-4-(1H-tetrazol-5-yl)piperidine; 1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-(1H-tetrazol-5-yl)piperidine. In another embodiment, preferred agents can be: ethyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-piperidine-carboxylate, otherwise known as SC-56938; [4-[5-(3-Phenyl-propyl)thiophen-2-yl]butoxy]acetic acid, otherwise known as RP64966; (R)—S-[[4-(dimethylamino)phenyl]methyl]-N-(3-mercapto-2methyl-1-oxopropyl-L-cycteine, otherwise known as SA6541. In one preferred embodiment, the therapeutic agent is 4-{(S)-2-[4-(4-Chloro-phenoxy)-phenoxymethyl]-pyrrolidin-1-yl}-butyramide, also known as DG-051.

The agents for treating or preventing coronary artery disease and/or myocardial infarction can be adminstered alone, or in combination with a statin. Statins include, but are not limited to, the agents rovuvastatin, fluvastatin, atorvastatin, lovastatin (also known as mevolin), simvastatin, pravastatin, pitavastatin, mevastatin, crevastatin, ML-236A, ML-236B, MBV-530A and MB-530B.

All agents listed in the above and in Agent Table I and Agent Table II also include their optically pure enantiomers, salts, chemical derivatives, and analogues.

AGENT TABLE I Date Patent Issued/ Product_Name Application (Code) Structure Chemical Name Patent Ref Published MOA Abbott atreleuton (ABT-761)

(R)-(+)-N-[3[5-[(4- fluorophenyl)methyl]-2thienyl]- 1 methyl-2-propynyl]-N- hydroxurea U.S. Pat. No. 5,288,751, U.S. Pat. No. 5,288,743, U.S. Pat. No. 5,616,596 Feb. 22, 1994 Apr. 1, 1997 5-LPO inhibitor Abbott A-81834

3-(3-(1,1-dimethylethylthio-5- 3-(quinoline-2-ylmethoxy)-1-(4- chloromethylphenyl)indo1e-2-yl) 2,2-dirnethylpropionaldehyde oxime-0-2-acetic acid WO9203132, U.S. Pat. No. 5,459,150 Mar. 5, 1992, Oct. 17, 1995 FLAP Inhibitor Abbott A-86886

3-(3-(1,1-dirnethylethylthlo-5- (pyridin-2-ylmathoxy)-1-(4- chloromethylphenyl)indole-2-yl)- 2,2-dimethylpropionaldehyde oxime-0-2-acetic acid W052031 32, U.S. Pat. No. 5,459,150 Mar. 5,1992, Oct. 17, 1995 5-LP0 Inhibitor Abbott A-93178

FLAP inhibitor AstraZeneca

EP 623514 Sep. 11, 1994 9-LPO inhibitor AstraZenaca ZD2138

6-((3-f1uoro-5- (tetrahydro-4-methoxy-2H- pyran-4yl)phenoxy)methyl) 1-methyl-2(1H)-quinlolinone (alternatively NH can be N-methyl) EP 466452 5-LPO inhibitor Bayer BAY-X-1005

(R)-(+)-alpha-cyclopentyl 4-(2-quinolinylmethoxy)- Benzeneacetic acid U.S. Pat. No. 4,970,215 EP 344519, DE 19880531 FLAP Inhibitor Merck MK-0591

1-((4-chlorophenyl)methyl)-3- ((1,1-dimethylethyl)thio)alpha, alpha-dimethyl-5-(2-quinolinylmethoxy)-1H-Indole-2-propanoic acid EP 419049, U.S. Pat. No. 19,890,822 FLAP Inhibitor Merck MK-866 (3(3-)-4-chlorobenzyl)-3-t-butyl- thio-5-isopropylindol-2-yl]2,2- dimethyl-propionic acid 5-LPO inhibitor Merck MK-886

1-((4- chlorophenyl)methyl)-3- ((1,1dimethylethyl)thio)- alpha, alpha-dimethyl-5-(2-quinolinylmethoxy)-1H- Indole-2-propanoic acid EP 419049, U.S. Pat. No. 19,890,822 5-LPO inhibitor Pfizer CJ-13610 4-(3-(4-(2-Methyl-imidazol-1-yl)- phenylsulfanyl)-phenyl)-tetrahydro-pyran-4- carboxylic acid amide 5-LPO inhibitor

AGENT TABLE II Compound Target ID Chemical Name Patent/Reference LTA4H SC-57461A 3-[methyl[3-[4- Penning, T.D. et. al. Bioorg Med. Inhibitor (phenylmethyl)phenoxy]- Chem. Letters (2003), 13, 1137-1139. propyl]amino]propionic ibid, (2002), 12, 3383-3386 acid LTA4H SC-56938 Ethyl-1-[2-[4- Penning, T.D. et. al. Bioorg Med. Inhibitor (phenylmethyl)phenoxy]ethyl]- Chem. Letters (2003), 13, 1137-1139. 4-piperidine- ibid, (2002), 12, 3383-3386. carboxylate U.S. Pat. No. 6,506,87 6A1 LTA4H RP 64966 [4-[5-(3-Phenyl- WO9627585 Inhibitor propyl)thiophen-2- yl]butoxy]acetic acid LTA4H SA 6541 (R)—S-[[4- WO9809943 Inhibitor (dimethylamino)phenyl]methyl]- N-(3-mercapto- 2methyl-1-oxopropyl-L- cycteine LTA4H SA-9499/ (R)-3-(4-Dimethylamino- Inhibitor SA-6541 benzylsulfanyl)-2-((R)-3- mercapto-2-methyl- propionylamino)-propionic acid LTB4 Amelubant/ Carbamic acid,((4-((3-((4- U.S. Pat. No. 6,576,669 Receptor BIIL-284 (1-(4-hydroxyphenyl)-1- Antagonist methylethyl)phenoxy)methyl)phenyl)methoxy)- phenyl)iminomethyl)ethyl ester LTB4 BIRZ-227 5-Chloro-2-[3-(4- Journal of Organic Chemistry Receptor methoxy-phenyl)-2- 1998, 63: 2(326-330). Antagonist pyridin-2-yl-pyrrolidin-1- yl]-benzooxazole LTB4 CP 195543 2-[(3S,4R)-3,4-dihydro-4- Process: WO 98/11085 1998, priority Receptor hydroxy-3- US 60/26372 1996; J. Antagonist (phenylmethyl)-2H-1- Pharamacology and Expert. Therapy, benzopyran-7-yl]-4- 1998, 285: 946-54 (trifluoromethyl)benzoic acid LTB4 Ebselen 2-Phenyl- Journal of Cerebral Blood Flow and Receptor benzo[d]isoselenazol-3- Metabolism 1995, July 2-6 (S162); Antagonist one Drugs of the Future 1995, 20: 10 (1057) LTB4 LTB 019; 4-[5-(4-Carbamimidoyl- ACS Meeting 1994, 207th: San Diego Receptor CGS- phenoxy)-pentyloxy]-N,N- (MEDI 003); International Congress Antagonist 25019C diisopropyl-3-methoxy- of the Inflammation Research benzamide maleate Association 1994, 7th: White Haven (Abs W23) LTB4 LY 210073 5-(2-Carboxy-ethyl)-6-[6- J Med Chem 1993 36 (12) 1726-1734 Receptor (4-methoxy-phenyl)-hex- Antagonist 5-enyloxy]-9-oxo-9H- xanthene-2-carboxylic acid LTB4 LY 213024 5-(3-carboxybenzoyl)-2- J Med Chem 1993 36 (12) 1726-1734 Receptor (decyloxy)benzenepropanoic Antagonist acid LTB4 LY 255283 1-[5-ethyl-2-hydroxy-4- EP 276064 B 1990, priority US 2479 Receptor [[6-methyl-6-(1H- 1987 Antagonist tetrazol-5- yl)heptyl]oxy]phenyl]ethanone LTB4 LY 264086 7-carboxy-3-(decyloxy)-9- U.S. Pat. No. 4,996,230 1991, priority US 481413 Receptor oxo-9H-xanthene-4- 1990 Antagonist propanoic acid LTB4 LY 292728 7-carboxy-3-[3-[(5-ethyl- EP 743064 A 1996, priority US Receptor 4′-fluoro-2-hydroxy[1,1′- 443179 1995 Antagonist biphenyl]-4-yl)oxy]propoxy]- 9-oxo-9H- xanthene-4-propanoic acid disodium salt LTB4 LY-293111 Benzoic acid,2-(3-(3-((5- Proceedings of the American Society Receptor (VML-295) ethyl-4′-fluoro-2- for Clinical Oncology 2002, 21: 1 Antagonist hydroxy(1,1′-biphenyl)-4- (Abs 343) [LY-293111 for Cancer] yl)oxy)propoxy)-2- SCRIP World Pharmaceutical News propylphenoxy)- 1997, 2272 (13) [for VML-295] LTB4 ONO 4057; (E)-2-(4-carboxybutoxy)- EP 405116 A 1991 Receptor LB 457 6-[[6-(4-methoxyphenyl)- Antagonist 5- hexenyl]oxy]benzenepropanoic acid LTB4 PF 10042 1-[5-hydroxy-5-[8-(1- EP 422329 B 1995, priority US Receptor hydroxy-2-phenylethyl)-2- 409630 1989 Antagonist dibenzofuranyl]-1-oxo pentyl]pyrrolidine LTB4 RG-14893 8-Benzyloxy-4-[(methyl- SCRIP World Pharmaceutical News Receptor phenethyl-carbamoyl)- 1996, 2168 (20) Antagonist methyl]-naphthalene-2- carboxylic acid LTB4 SB-201993 3-{6-(2-Carboxy-vinyl)-5- WO-09500487 Receptor [8-(4-methoxy-phenyl)- Antagonist octyloxy]-pyridin-2- ylmethylsulfanylmethyl}- benzoic acid LTB4 SC-52798 7-[3-(2- Bioorganic and Medicinal Chemistry Receptor Cyclopropylmethyl-3- Letters 1994, 4: 6 (811-816); Journal Antagonist methoxy-4-thiazol-4-yl- of Medicinal Chemistry 1995, 38: 6 phenoxy)-propoxy]-8- (858-868) propyl-chroman-2- carboxylic acid LTB4 SC-53228 3-{7-[3-(2- International Congress of the Receptor Cyclopropylmethyl-3- Inflammation Research Association Antagonist methoxy-4- 1994, 7th: White Haven (Abs W5) methylcarbamoyl- phenoxy)-propoxy]-8- propyl-chroman-2-yl}- propionic acid LTB4 WAY 3-fluoro-4′-(2- Drugs under Experimental and Clinical Receptor 121006 quinolinylmethoxy)-[1,1′- research 1991, 17: 8 (381-387) Antagonist biphenyl]-4-acetic acid LTB4 ZD-2138 3-Amino-3-(4-methoxy- International Symposium on Medicinal Receptor tetrahydro-pyran-4-yl)- Chemistry 1994, 13th: Paris (P 197) Antagonist acrylic acid 1-methyl-2- oxo-1,2-dihydro-quinolin- 6-ylmethyl ester

Alternatively, biological networks or metabolic pathways related to the markers and haplotypes of the present invention can be monitored by determining mRNA and/or polypeptide levels. This can be done for example, by monitoring expression levels or polypeptides for several genes belonging to the network and/or pathway, in samples taken before and during treatment. Alternatively, metabolites belonging to the biological network or metabolic pathway can be determined before and during treatment. Effectiveness of the treatment is determined by comparing observed changes in expression levels/metabolite levels during treatment to corresponding data from healthy subjects.

In a further aspect, the markers of the present invention can be used to increase power and effectiveness of clinical trials. Thus, individuals who are carriers of the at-risk variants of the present invention may be more likely to respond to a particular treatment modality. In one embodiment, individuals who carry at-risk variants for gene(s) in a pathway and/or metabolic network for which a particular treatment (e.g., small molecule drug, e.g. the small molecule drugs as listed in the above, e.g., the drugs listed in Agent Table I and Agent Table II) is targeting, are more likely to be responders to the treatment. In another embodiment, individuals who carry at-risk variants for a gene, which expression and/or function is altered by the at-risk variant, are more likely to be responders to a treatment modality targeting that gene, its expression or its gene product.

In a further aspect, the markers and haplotypes of the present invention can be used for targeting the selection of pharmaceutical agents for specific individuals. Personalized selection of treatment modalities, lifestyle changes (e.g., change in diet, exercise, weight loss program, smoking abstinence, less stressful lifestyle, etc.) or combination of the two, can be realized by the utilization of the at-risk variants of the present invention. Thus, the knowledge of an individual's status for particular markers of the present invention, can be useful for selection of treatment options that target genes or gene products affected by the at-risk variants of the invention. Certain combinations of variants may be suitable for one selection of treatment options, while other gene variant combinations may target other treatment options. Such combination of variant may include one variant, two variants, three variants, or four or more variants, as needed to determine with clinically reliable accuracy the selection of treatment module.

Computer-Implemented Aspects

The present invention also relates to computer-implemented applications of the polymorphic markers and haplotypes described herein to be associated with coronary artery disease and myocardial infarction. Such applications can be useful for storing, manipulating or otherwise analyzing genotype data that is useful in the methods of the invention. One example pertains to storing genotype information derived from an individual on readable media, so as to be able to provide the genotype information to a third party (e.g., the individual), or for deriving information from the genotype data, e.g., by comparing the genotype data to information about genetic risk factors contributing to increased susceptibility to coronary artery disease and/or myocardial infarction, and reporting results based on such comparison.

One such aspect relates to computer-readable media. In general terms, such medium has capabilities of storing (i) identifier information for at least one polymorphic marker or a haplotype; (ii) an indicator of the frequency of at least one allele of said at least one marker, or the frequency of a haplotype, in individuals with coronary artery disease and/or myocardial infarction; and an indicator of the frequency of at least one allele of said at least one marker, or the frequency of a haplotype, in a reference population. The reference population can be a disease-free population of individuals. Alternatively, the reference population is a random sample from the general population, and is thus representative of the population at large. The frequency indicator may be a calculated frequency, a count of alleles and/or haplotype copies, or normalized or otherwise manipulated values of the actual frequencies that are suitable for the particular medium.

Additional information about the individual can be stored on the medium, such as ancestry information, information about sex, physical attributes or characteristics (including height and weight), biochemical measurements (such as blood pressure, blood lipid levels, lipid levels, such as cholesterol levels), biomarkers relevant for cardiovascular disease, as described further herein, or other useful information that is desirable to store or manipulate in the context of the genotype status of a particular individual.

The invention furthermore relates to an apparatus that is suitable for determination or manipulation of genetic data useful for determining a susceptibility to coronary artery disease and/or myocardial infarction in a human individual. Such an apparatus can include a computer-readable memory, a routine for manipulating data stored on the computer-readable memory, and a routine for generating an output that includes a measure of the genetic data. Such measure can include values such as allelic or haplotype frequencies, genotype counts, sex, age, phenotype information, values for odds ratio (OR) or relative risk (RR), population attributable risk (PAR), or other useful information that is either a direct statistic of the original genotype data or based on calculations based on the genetic data.

The markers and haplotypes shown herein to be associated with increased susceptibility (e.g., increased risk) of cardiovascular disease, are in certain embodiments useful for interpretation and/or analysis of genotype data. Thus in certain embodiments, an identification of an at-risk allele for coronary artery disease and/or myocardial infarction, as shown herein, or an allele at a polymorphic marker in LD with any one of the markers shown herein to be associated with coronary artery disease and/or myocardial infarction, is indicative of the individual from whom the genotype data originates is at increased risk of coronary artery disease and/or myocardial infarction. In one such embodiment, genotype data is generated for at least one polymorphic marker shown herein to be associated with coronary artery disease and/or myocardial infarction, or a marker in linkage disequilibrium therewith. The genotype data is subsequently made available to a third party, such as the individual from whom the data originates, for example via a user interface accessible over the internet, together with an interpretation of the genotype data, e.g., in the form of a risk measure (such as an absolute risk (AR), risk ratio (RR) or odds ration (OR)) for the cardiovascular disease. In another embodiment, at-risk markers identified in a genotype dataset derived from an individual are assessed and results from the assessment of the risk conferred by the presence of such at-risk variants in the dataset are made available to the individual, for example via a secure web interface, or by other communication means. The results of such risk assessment can be reported in numeric form (e.g., by risk values, such as absolute risk, relative risk, and/or an odds ratio, or by a percentage increase in risk compared with a reference), by graphical means, or by other means suitable to illustrate the risk to the individual from whom the genotype data is derived. In particular embodiments, the results of risk assessment is made available to a third party, e.g., a physician, other healthcare worker or genetic counselor.

Markers Useful in Various Aspects of the Invention

The above-described applications can all be practiced with the markers and haplotypes of the invention that have in more detail been described with respect to methods of assessing susceptibility to cardiovascular disease and described in detail herein. Thus, these applications can in general be reduced to practice using any of the markers listed in Tables 1-5 herein, and markers in linkage disequilibrium therewith. In some embodiments, the markers are selected from the markers set forth in Table 3, and markers in linkage disequilibrium therewith. In some other embodiments, the markers are selected from the markers set forth in Table 4, and markers in linkage disequilibrium therewith. In some other embodiments, the markers are selected from the markers rs11751605 (SEQ ID NO:1), rs6076623 (SEQ ID NO:2), rs1412444 (SEQ ID NO:3), rs2163612 (SEQ ID NO:4), rs1029396 (SEQ ID NO:5), rs2243547 (SEQ ID NO:6), rs12534186 (SEQ ID NO:7), rs12134779 (SEQ ID NO:8) and rs7158073 (SEQ ID NO:9), and markers in linkage disequilibrium therewith. In some other embodiments, the markers are selected from the markers rs11751605 (SEQ ID NO:1), rs6076623 (SEQ ID NO:2), rs1412444 (SEQ ID NO:3), rs2163612 (SEQ ID NO:4), and rs1029396 (SEQ ID NO:5), and markers in linkage disequilibrium therewith. In some preferred embodiments, the marker is selected from rs11751605 (SEQ ID NO:1), and markers in linkage disequilibrium therewith. In other preferred embodiments, the marker is selected from rs6076623 (SEQ ID NO:2), and markers in linkage disequilibrium therewith. In yet other preferred embodiments, the marker is selected from rs1412444 (SEQ ID NO:3), and markers in linkage disequilibrium therewith. In other preferred embodiments, the marker is selected from rs2163612 (SEQ ID NO:4), and markers in linkage disequilibrium therewith. The marker may also be selected from rs1029396 (SEQ ID NO:5), and markers in linkage disequilibrium therewith. In a particularly preferred embodiment, the marker is rs11751605 (SEQ ID NO:1). In preferred embodiments, linkage disequilibrium between markers is defined by numerical values for r² of greater than 0.2.

In some embodiments, the presence of allele C in rs11751605, allele T in rs6076623, allele A in rs1412444, allele G in rs2163612 or allele G in rs1029396 is indicative of increased susceptibility of coronary artery disease or myocardial infarction in the individual who is undergoing testing, through analysis of genotype information (genotype dataset) derived from the individual, or through analysis of a sample comprising genomic DNA from the individual.

Nucleic Acids and Polypeptides

The nucleic acids and polypeptides described herein can be used in methods and kits of the present invention. An “isolated” nucleic acid molecule, as used herein, is one that is separated from nucleic acids that normally flank the gene or nucleotide sequence (as in genomic sequences) and/or has been completely or partially purified from other transcribed sequences (e.g., as in an RNA library). For example, an isolated nucleic acid of the invention can be substantially isolated with respect to the complex cellular milieu in which it naturally occurs, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized. In some instances, the isolated material will form part of a composition (for example, a crude extract containing other substances), buffer system or reagent mix. In other circumstances, the material can be purified to essential homogeneity, for example as determined by polyacrylamide gel electrophoresis (PAGE) or column chromatography (e.g., HPLC). An isolated nucleic acid molecule of the invention can comprise at least about 50%, at least about 80% or at least about 90% (on a molar basis) of all macromolecular species present. With regard to genomic DNA, the term “isolated” also can refer to nucleic acid molecules that are separated from the chromosome with which the genomic DNA is naturally associated. For example, the isolated nucleic acid molecule can contain less than about 250 kb, 200 kb, 150 kb, 100 kb, 75 kb, 50 kb, 25 kb, 10 kb, 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of the nucleotides that flank the nucleic acid molecule in the genomic DNA of the cell from which the nucleic acid molecule is derived.

The nucleic acid molecule can be fused to other coding or regulatory sequences and still be considered isolated. Thus, recombinant DNA contained in a vector is included in the definition of “isolated” as used herein. Also, isolated nucleic acid molecules include recombinant DNA molecules in heterologous host cells or heterologous organisms, as well as partially or substantially purified DNA molecules in solution. “Isolated” nucleic acid molecules also encompass in vivo and in vitro RNA transcripts of the DNA molecules of the present invention. An isolated nucleic acid molecule or nucleotide sequence can include a nucleic acid molecule or nucleotide sequence that is synthesized chemically or by recombinant means. Such isolated nucleotide sequences are useful, for example, in the manufacture of the encoded polypeptide, as probes for isolating homologous sequences (e.g., from other mammalian species), for gene mapping (e.g., by in situ hybridization with chromosomes), or for detecting expression of the gene in tissue (e.g., human tissue), such as by Northern blot analysis or other hybridization techniques.

The invention also pertains to nucleic acid molecules that hybridize under high stringency hybridization conditions, such as for selective hybridization, to a nucleotide sequence described herein (e.g., nucleic acid molecules that specifically hybridize to a nucleotide sequence containing a polymorphic site associated with a haplotype described herein). In one embodiment, the invention includes variants that hybridize under high stringency hybridization and wash conditions (e.g., for selective hybridization) to a nucleotide sequence that comprises the nucleotide sequence according to any one of SEQ ID NO:1-172 or a fragment thereof (or a nucleotide sequence comprising the complement of the nucleotide sequence of any one of SEQ ID NO:1-172), wherein the nucleotide sequence comprises at least one at-risk allele of at least one polymorphic marker, or at least one haplotype, as described herein.

The percent identity of two nucleotide or amino acid sequences can be determined by aligning the sequences for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first sequence). The nucleotides or amino acids at corresponding positions are then compared, and the percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity=# of identical positions/total # of positions×100). In certain embodiments, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%, of the length of the reference sequence. The actual comparison of the two sequences can be accomplished by well-known methods, for example, using a mathematical algorithm. A non-limiting example of such a mathematical algorithm is described in Karlin, S, and Altschul, S., Proc. Natl. Acad. Sci. USA, 90:5873-5877 (1993). Such an algorithm is incorporated into the NBLAST and XBLAST programs (version 2.0), as described in Altschul, S. et al., Nucleic Acids Res., 25:3389-3402 (1997). When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., NBLAST) can be used. See the website on the world wide web at ncbi.nlm.nih.gov. In one embodiment, parameters for sequence comparison can be set at score=100, wordlength=12, or can be varied (e.g., W=5 or W=20). Another example of an algorithm is BLAT (Kent, W. J. Genome Res. 12:656-64 (2002)).

The present invention also provides isolated nucleic acid molecules that contain a fragment or portion that hybridizes under highly stringent conditions to a nucleic acid that comprises, or consists of, the nucleotide sequence of any one of SEQ ID NO:1-172, or a nucleotide sequence comprising, or consisting of, the complement of the nucleotide sequence of any one of SEQ ID NO:1-172, wherein the nucleotide sequence comprises at least one polymorphic allele contained in the markers and haplotypes described herein. The nucleic acid fragments of the invention are at least about 15, at least about 18, 20, 23 or 25 nucleotides, and can be 30, 40, 50, 100, 200, 500, 1000, 10,000 or more nucleotides in length.

The nucleic acid fragments of the invention are used as probes or primers in assays such as those described herein. “Probes” or “primers” are oligonucleotides that hybridize in a base-specific manner to a complementary strand of a nucleic acid molecule. In addition to DNA and RNA, such probes and primers include polypeptide nucleic acids (PNA), as described in Nielsen, P. et al., Science 254:1497-1500 (1991). A probe or primer comprises a region of nucleotide sequence that hybridizes to at least about 15, typically about 20-25, and in certain embodiments about 40, 50 or 75, consecutive nucleotides of a nucleic acid molecule comprising a contiguous nucleotide sequence from any one of SEQ ID NO:1-172 and comprising at least one allele of at least one polymorphic marker or at least one haplotype described herein, or the complement thereof. In particular embodiments, a probe or primer can comprise 100 or fewer nucleotides; for example, in certain embodiments from 6 to 50 nucleotides, or, for example, from 12 to 30 nucleotides. In other embodiments, the probe or primer is at least 70% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to the contiguous nucleotide sequence or to the complement of the contiguous nucleotide sequence. In another embodiment, the probe or primer is capable of selectively hybridizing to the contiguous nucleotide sequence or to the complement of the contiguous nucleotide sequence. Often, the probe or primer further comprises a label, e.g., a radioisotope, a fluorescent label, an enzyme label, an enzyme co-factor label, a magnetic label, a spin label, an epitope label.

The nucleic acid molecules of the invention, such as those described above, can be identified and isolated using standard molecular biology techniques and the sequence information provided by the nucleotide sequence of any one of SEQ ID NO:1-172. See generally PCR Technology: Principles and Applications for DNA Amplification (ed. H.A. Erlich, Freeman Press, NY, N.Y., 1992); PCR Protocols: A Guide to Methods and Applications (Eds. Innis, et al., Academic Press, San Diego, Calif., 1990); Mattila, P. et al., Nucleic Acids Res., 19:4967-4973 (1991); Eckert, K. and Kunkel, T., PCR Methods and Applications, 1:17-24 (1991); PCR (eds. McPherson et al., IRL Press, Oxford); and U.S. Pat. No. 4,683,202, the entire teachings of each of which are incorporated herein by reference.

Antibodies

Polyclonal antibodies and/or monoclonal antibodies that specifically bind one form of the gene product but not to the other form of the gene product (such as Lipoprotein(a), including kringle IV variants of Lipoprotein(a)) are also provided. Antibodies are also provided which bind a portion of either the variant or the reference gene product that contains the polymorphic site or sites. The term “antibody” as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain antigen-binding sites that specifically bind an antigen. A molecule that specifically binds to a polypeptide of the invention is a molecule that binds to that polypeptide or a fragment thereof, but does not substantially bind other molecules in a sample, e.g., a biological sample, which naturally contains the polypeptide. Examples of immunologically active portions of immunoglobulin molecules include F(ab) and F(ab′)₂ fragments which can be generated by treating the antibody with an enzyme such as pepsin. The invention provides polyclonal and monoclonal antibodies that bind to a polypeptide of the invention. The term “monoclonal antibody” or “monoclonal antibody composition”, as used herein, refers to a population of antibody molecules that contain only one species of an antigen binding site capable of immunoreacting with a particular epitope of a polypeptide of the invention. A monoclonal antibody composition thus typically displays a single binding affinity for a particular polypeptide of the invention with which it immunoreacts.

Polyclonal antibodies can be prepared as described above by immunizing a suitable subject with a desired immunogen, e.g., polypeptide of the invention or a fragment thereof. The antibody titer in the immunized subject can be monitored over time by standard techniques, such as with an enzyme linked immunosorbent assay (ELISA) using immobilized polypeptide. If desired, the antibody molecules directed against the polypeptide can be isolated from the mammal (e.g., from the blood) and further purified by well-known techniques, such as protein A chromatography to obtain the IgG fraction. At an appropriate time after immunization, e.g., when the antibody titers are highest, antibody-producing cells can be obtained from the subject and used to prepare monoclonal antibodies by standard techniques, such as the hybridoma technique originally described by Kohler and Milstein, Nature 256:495-497 (1975), the human B cell hybridoma technique (Kozbor et al., Immunol. Today 4: 72 (1983)), the EBV-hybridoma technique (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, 1985, Inc., pp. 77-96) or trioma techniques. The technology for producing hybridomas is well known (see generally Current Protocols in Immunology (1994) Coligan et al., (eds.) John Wiley & Sons, Inc., New York, N.Y.). Briefly, an immortal cell line (typically a myeloma) is fused to lymphocytes (typically splenocytes) from a mammal immunized with an immunogen as described above, and the culture supernatants of the resulting hybridoma cells are screened to identify a hybridoma producing a monoclonal antibody that binds a polypeptide of the invention.

Any of the many well known protocols used for fusing lymphocytes and immortalized cell lines can be applied for the purpose of generating a monoclonal antibody to a polypeptide of the invention (see, e.g., Current Protocols in Immunology, supra; Galfre et al., Nature 266:55052 (1977); R. H. Kenneth, in Monoclonal Antibodies: A New Dimension In Biological Analyses, Plenum Publishing Corp., New York, N.Y. (1980); and Lerner, Yale J. Biol. Med. 54:387-402 (1981)). Moreover, the ordinarily skilled worker will appreciate that there are many variations of such methods that also would be useful.

Alternative to preparing monoclonal antibody-secreting hybridomas, a monoclonal antibody to a polypeptide of the invention can be identified and isolated by screening a recombinant combinatorial immunoglobulin library (e.g., an antibody phage display library) with the polypeptide to thereby isolate immunoglobulin library members that bind the polypeptide. Kits for generating and screening phage display libraries are commercially available (e.g., the Pharmacia Recombinant Phage Antibody System, Catalog No. 27-9400-01; and the Stratagene SurfZAP™ Phage Display Kit, Catalog No. 240612). Additionally, examples of methods and reagents particularly amenable for use in generating and screening antibody display library can be found in, for example, U.S. Pat. No. 5,223,409; PCT Publication No. WO 92/18619; PCT Publication No. WO 91/17271; PCT Publication No. WO 92/20791; PCT Publication No. WO 92/15679; PCT Publication No. WO 93/01288; PCT Publication No. WO 92/01047; PCT Publication No. WO 92/09690; PCT Publication No. WO 90/02809; Fuchs et al., Bio/Technology 9: 1370-1372 (1991); Hay et al., Hum. Antibod. Hybridomas 3:81-85 (1992); Huse et al., Science 246: 1275-1281 (1989); and Griffiths et al., EMBO J. 12:725-734 (1993).

Additionally, recombinant antibodies, such as chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, which can be made using standard recombinant DNA techniques, are within the scope of the invention. Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art.

In general, antibodies of the invention (e.g., a monoclonal antibody) can be used to isolate a polypeptide of the invention by standard techniques, such as affinity chromatography or immunoprecipitation. A polypeptide-specific antibody can facilitate the purification of natural polypeptide from cells and of recombinantly produced polypeptide expressed in host cells. Moreover, an antibody specific for a polypeptide of the invention can be used to detect the polypeptide (e.g., in a cellular lysate, cell supernatant, or tissue sample) in order to evaluate the abundance and pattern of expression of the polypeptide. Antibodies can be used diagnostically to monitor protein levels in tissue as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. The antibody can be coupled to a detectable substance to facilitate its detection. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include ¹²⁵I, ¹³¹I, ³⁵S or ³H.

Antibodies may also be useful in pharmacogenomic analysis. In such embodiments, antibodies against variant proteins encoded by nucleic acids according to the invention (for example, variant forms of Lipoprotein(a), such as kringle IV repeat polymorphisms), such as variant proteins that are encoded by nucleic acids that contain at least one polymorphic marker of the invention, can be used to identify individuals that require modified treatment modalities.

Antibodies can furthermore be useful for assessing expression of variant proteins in disease states, such as in active stages of a cardiovascular disease, or in an individual with a predisposition to a disease related to the function of the protein, in particular a cardiovascular disease. Examples are provided by biomarker (e.g., cardiac markers), as described further herein. Antibodies specific for a variant protein of the present invention that is encoded by a nucleic acid that comprises at least one polymorphic marker or haplotype as described herein (e.g., CDKN2A and/or CDKN2B) can be used to screen for the presence of the variant protein, for example to screen for a predisposition to cardiovascular disease as indicated by the presence of the variant protein.

Antibodies can be used in other methods. Thus, antibodies are useful as diagnostic tools for evaluating proteins, such as variant proteins of the invention (e.g., variants of Lipoprotein(a), such as kringle IV repeat variants), in conjunction with analysis by electrophoretic mobility, isoelectric point, tryptic or other protease digest, or for use in other physical assays known to those skilled in the art. Antibodies may also be used in tissue typing. In one such embodiment, a specific variant protein has been correlated with expression in a specific tissue type, and antibodies specific for the variant protein can then be used to identify the specific tissue type.

Subcellular localization of proteins, including variant proteins, can also be determined using antibodies, and can be applied to assess aberrant subcellular localization of the protein in cells in various tissues. Such use can be applied in genetic testing, but also in monitoring a particular treatment modality. In the case where treatment is aimed at correcting the expression level or presence of the variant protein or aberrant tissue distribution or developmental expression of the variant protein, antibodies specific for the variant protein or fragments thereof can be used to monitor therapeutic efficacy.

Antibodies are further useful for inhibiting variant protein function (e.g., Lipoprotein(a)), for example by blocking the binding of a variant protein to a binding molecule or partner. Such uses can also be applied in a therapeutic context in which treatment involves inhibiting a variant protein's function. An antibody can be for example be used to block or competitively inhibit binding, thereby modulating (i.e., agonizing or antagonizing) the activity of the protein. Antibodies can be prepared against specific protein fragments containing sites required for specific function or against an intact protein that is associated with a cell or cell membrane. For administration in vivo, an antibody may be linked with an additional therapeutic payload, such as radionuclide, an enzyme, an immunogenic epitope, or a cytotoxic agent, including bacterial toxins (diphtheria or plant toxins, such as ricin). The in vivo half-life of an antibody or a fragment thereof may be increased by pegylation through conjugation to polyethylene glycol.

The present invention further relates to kits for using antibodies in the methods described herein. This includes, but is not limited to, kits for detecting the presence of a variant protein in a test sample. One preferred embodiment comprises antibodies such as a labelled or labelable antibody and a compound or agent for detecting variant proteins in a biological sample, means for determining the amount or the presence and/or absence of variant protein in the sample, and means for comparing the amount of variant protein in the sample with a standard, as well as instructions for use of the kit.

The present invention will now be exemplified by the following non-limiting examples.

EXEMPLIFICATION Example 1

The following contains description of the identification of susceptibility factors found to be associated with coronary artery disease and myocardial infarction through single-point analysis of SNP markers and microsatellite markers.

Methods

The study was approved by the Data Protection Commission of Iceland and the National Bioethics Committee.

Icelandic Coronary Artery Disease Cohort

Over the last eight years individuals who have suffered an MI we have been recruited through cardiovascular disease (CVD) genetic programs at deCODE. Currently blood samples have been collected from 2525 MI patients. The individuals who had suffered an MI were identified from a registry of over 10,000 individuals who: a) had an MI before the age of 75 in Iceland in the years 1981 to 2002 and satisfy the MONICA criteria (J Clin Epidemiol 41, 105-14 (1988)); b) participated in a large prospective epidemiology study (1) done by the Icelandic Heart Association (IHA) over the past 30 years and had MI prior to 1981; c) had MI discharge diagnosis from the major hospitals in Reykjavik in the years 2003 and 2004. MI diagnoses of all individuals in the registry follow strict diagnostic rules based on signs, symptoms, electrocardiograms, cardiac enzymes and necropsy findings (2). The patients were contacted through collaborating physicians in the CVD genetic programs at deCODE. Most of the participants in the study visited the IHA and had their blood drawn, although participants who lived outside the Reykjavik area visited their local health care center.

Additional subjects with coronary artery disease, but are without known history of myocardial infarction, are identified from a list of those who have undergone coronary stent procedure in the major hospitals in Reykjavik in the years 1993 and 2003.

The controls used for the study were recruited as a part of various genetic programs at deCODE. The medical history for the controls were unknown unless if the control subjects also had participated in any of the CVD genetic programs (i.e. MI, stroke, peripheral vascular disease, type II diabetes, obesity, familial combined hyperlipidemia, coronary restenosis, and hypertension genetic programs). Individuals with known MI, stroke, peripheral vascular or coronary artery disease were excluded as controls.

Subjects from the United States Cohort from Philadelphia

The study participants from Philadelphia were enrolled at the University of Pennsylvania Medical Center through the PENN CATH study program which studies the association of biochemical and genetic factors to coronary artery disease (CAD) in subjects undergoing cardiac catheterization. A total of 3850 subjects have participated. For the purpose of the current study we selected from the PENN CATH study individuals diagnosed with one of the following coronary artery disease: MI based on criteria for acute MI in terms of elevations of cardiac enzymes and electrocardiographic changes, or a self-reported history of MI, history of coronary artery bypass surgery (CABG) or percutaneous, transluminal coronary angioplasty (PTCA). To use as controls we selected individuals who were without significant luminal stenosis on coronary angiography (luminal stenosis less than 50%). Ethnicity information was self-reported.

The University of Pennsylvania Institutional Review Board approved the study and all subjects provided written informed consent.

Cohort from Durham, N.C.

The study participants were enrolled at Duke University Medical Center (Durham, N.C.) through the CATHGEN biorepository, recruited sequentially through the cardiac catheterization laboratories from 2001-2005. Biological samples and extensive clinical, angiographic, and longitudinal follow-up data were collected on all subjects consenting to participation. For purposes of this study, cases of MI were defined as those having a history of MI (by self-report and corroborated by review of medical records), or having suffered an MI during the study follow-up period. Controls from this cohort, defined as those with no history of MI prior or subsequent to the index cardiac catheterization, as well as no history of percutaneous or surgical coronary revascularization procedure; no subsequent percutaneous or surgical coronary revascularization procedures; ejection fraction on left ventriculogram greater than 40%; and no or minimal CAD on coronary angiography (defined as a CAD index less than or equal to 23 and no coronary vessel with clinically significant CAD (stenosis greater than 50%)). This study was approved by the Duke University Medical Center Institutional Review Board on Human Subjects and all subjects gave written informed consent.

Cohort from Atlanta

The study participants were enrolled at the Emory University Hospital, the Emory Clinic and Grady Memorial Hospitals through its Emory Genebank study and Clinical Registry in Neurology (CRIN). The Emory Genebank studies the association of biochemical and genetic factors with CAD in subjects undergoing cardiac catheterization. For the purpose of the current study those subjects who had a self-reported history of MI, CABG, or PTCA, were selected and used as a patient group. Control subjects were selected from a group of individuals with non-vascular neurological diseases (mainly Parkinson's and Alzheimer's diseases) recruited from CRIN, their spouses, unrelated friends and community volunteers. These subjects were matched for age, and ethnicity to the patient population. Controls were excluded if they had a known history of MI or coronary artery disease. All subjects provided written informed consent. Information on ethnicity was self-reported.

Genotyping

A genome-wide scan of 1700 Icelandic individuals diagnosed with myocardial infarction (MI), 2034 patients with coronary artery disease and 10635 population controls was performed using Infinium HumanHap300 SNP chips from Illumina for assaying approximately 317,000 single nucleotide polymorphisms (SNPs) on a single chip (Illumina, San Diego, Calif., USA). SNP genotyping for replication in other case-control cohorts was carried using the Centaurus platform (Nanogen).

Statistical Methods for Association Analysis.

To test individual markers for association to disease phenotypes such as coronary artery disease or myocardial infarction, we use a likelihood ratio test to calculate a two-sided P-value for each allele of the markers. We calculate relative risk (RR) and population attributable risk (PAR) assuming a multiplicative model (C. T. Falk, P. Rubinstein, Ann Hum Genet 51 (Pt 3), 227 (1987); J. D. Terwilliger, J. Ott, Hum Hered 42, 337 (1992)). To elucidate the linkage disequilibrium between markers in the region we used the CEPH Caucasian HapMap data. We calculated LD between pairs of SNPs using the standard definition of D′ (R. C. Lewontin, Genetics 50, 757 (1964)) and for the correlation coefficient r² (W. G. Hill, A. Robertson, Genetics 60, 615 (November, 1968). For the Icelandic cohort, to take into account that some of the individuals are related to each other, we obtained the null statistic of the test statistic either by simulating genotypes through the Icelandic genealogy or from the test statistic for all the 300,000 tested for association in the initial genome-wide association scan (citation). Model-free estimates of the genotype relative risk are generated as follows: RR of genotype G₁ compared to genotype G₀ was estimated by [n(G₁)/n(G₀)]/[m(G₁)/m(G₀)] where n and m denote genotype counts in patients and controls respectively. Results from different cohorts were combined using a Mantel-Hanezel model (citation) where cohorts are allowed to have different population frequencies for the alleles/genotypes but assume to have common relative risks.

We use multiple regression to test for association between markers and quantitative traits, such as ago of onset of MI in the cases, where the number of copies of the at-risk variant carried by an individual is taken as explanatory variable and the quantitative trait as the response variable. The association is adjusted for age and gender, where appropriate, by including corresponding terms in the regression analysis as explanatory variables.

Results Genome-Wide Association Study

We successfully genotyped 1700 Icelandic myocardial infarction patients, 2034 coronary artery disease Patients and 10635 population control individuals without known history of coronary artery disease (Cohort A) using the Illumina 330K chip. We performed a genome-wide scan for association to MI, testing individually each of the 309,091 SNPs that was successfully genotyped. Results of this association analysis is presented in Table 1, wherein markers showing significant association to MI are indicated (p-value less than 0.01). As can be seen in the table, a large number of markers show significant association to MI, including markers rs2227165 on chromosome X, rs12304836 on chromosome 12 and rs11225090 on chromosome 11.

The markers found to be associating with MI as presented in Table 1 may be useful for risk assessment and diagnostic purposes for MI, either alone or in combination. Even in the cases where the increase in risk by individual markers is relatively modest, i.e. on the order of 15-30%, the association may have significant implications. Thus, relatively common variants may have significant contribution to the overall risk (Population Attributable Risk is high), or combination of markers can be used to define groups of individual who, based on the combined risk of the markers, is at significant combined risk of developing MI.

TABLE 1 Association results for SNPs showing association to Myoardial Infarction (MI) and coronary artery disease (CAD). The columns indicate (1) chromosome, (2) position in NCBI Build 34, (3) rs name of the SNP in question, (4), the associating allele, (5) frequency of the associating allele in controls, (6) the number of controls, (7), the p-value for association to MI, (8) the Relative Risk of association to MI, (9) the frequency of the associating allele in MI patients, (10) the number of MI patients, (11) the p-value of association to CAD, (12) the Relative Risk of association to CAD, (13) the frequency of the associating allele in CAD patients, (14) the number of CAD patients. The table is sorted on p- values for association to MI. chr position b34 rs-name allele f(con) N(con) p(MI) RR(MI) f(MI) N(MI) p(CAD) rr(CAD) f(CAD) N(CAD) CX 91765264 rs2227165 C 0.897 8178 2.08E−07 1.61 0.934 1068 5.16E−05 1.39 0.924 1276 C12 124441592 rs12304836 C 0.141 10541 7.66E−06 1.27 0.173 1689 6.26E−06 1.25 0.171 2020 C11 101370325 rs11225090 T 0.969 10513 8.71E−06 1.85 0.983 1646 2.95E−05 1.68 0.981 1979 C05 158504417 rs7442701 T 0.174 10629 1.05E−05 1.25 0.208 1699 5.90E−05 1.21 0.202 2033 C12 116419694 rs816204 A 0.851 10607 1.10E−05 1.29 0.881 1693 4.70E−05 1.25 0.877 2026 C20 4131671 rs6076623 T 0.364 10632 1.20E−05 1.19 0.406 1700 2.40E−06 1.19 0.406 2034 C17 17995010 rs4925125 T 0.347 10430 1.55E−05 1.19 0.388 1680 3.40E−04 1.15 0.379 2009 C10 90667504 rs1412444 A 0.356 10626 1.60E−05 1.19 0.397 1700 2.38E−04 1.15 0.389 2034 C17 18235585 rs854787 C 0.398 10568 1.72E−05 1.19 0.44 1689 2.63E−05 1.17 0.436 2023 C10 90675056 rs2243547 G 0.339 10200 1.82E−05 1.2 0.38 1642 3.87E−04 1.15 0.37 1970 C08 506479 rs722782 C 0.888 10607 2.44E−05 1.33 0.914 1668 1.72E−04 1.26 0.909 2002 C11 82905504 rs2163612 G 0.476 10625 3.12E−05 1.18 0.517 1698 3.92E−05 1.16 0.513 2032 C01 62766259 rs12134779 T 0.29 10634 3.21E−05 1.19 0.327 1699 1.81E−04 1.16 0.321 2033 CX 66228891 rs7050085 G 0.909 8267 5.71E−05 1.45 0.936 1103 1.15E−04 1.39 0.933 1316 C07 116846839 rs12534186 T 0.079 10631 5.99E−05 1.31 0.102 1699 2.22E−04 1.26 0.098 2033 C05 158510030 rs7447732 C 0.316 10635 6.14E−05 1.18 0.353 1700 3.34E−04 1.15 0.347 2034 C07 116800818 rs2299445 C 0.079 10630 6.16E−05 1.31 0.101 1699 2.21E−04 1.27 0.098 2033 C07 116800818 rs2299445 C 0.079 10630 6.16E−05 1.31 0.101 1699 2.21E−04 1.27 0.098 2033 C19 4229502 rs4807567 T 0.419 10586 6.30E−05 1.17 0.458 1699 1.99E−04 1.15 0.453 2033 C13 26936609 rs4769613 T 0.467 10633 6.56E−05 1.17 0.506 1699 9.01E−06 1.18 0.507 2033 C05 158671846 rs4921437 T 0.212 10594 6.57E−05 1.21 0.245 1691 6.09E−04 1.16 0.238 2023 C10 15439877 rs12269612 T 0.398 10634 6.66E−05 1.17 0.437 1700 8.04E−04 1.13 0.428 2034 C12 87995622 rs1568383 T 0.097 10635 7.05E−05 1.28 0.121 1700 1.11E−04 1.25 0.119 2034 C21 24038081 rs2828495 A 0.211 10635 7.27E−05 1.2 0.244 1700 4.74E−05 1.19 0.242 2034 C10 45239070 rs2279434 T 0.065 10634 7.50E−05 1.34 0.085 1700 5.02E−04 1.27 0.081 2033 C02 212588265 rs12329252 T 0.676 10635 7.87E−05 1.18 0.712 1700 6.42E−04 1.14 0.705 2034 C03 62420156 rs9874646 T 0.709 10634 8.11E−05 1.19 0.744 1700 3.83E−04 1.16 0.738 2034 C04 21568604 rs4282162 T 0.528 10633 8.28E−05 1.17 0.567 1700 1.66E−04 1.15 0.563 2034 C03 62402714 rs1534725 T 0.782 10627 8.33E−05 1.21 0.814 1699 1.33E−04 1.19 0.811 2033 C03 62402714 rs1534725 T 0.782 10627 8.33E−05 1.21 0.814 1699 1.33E−04 1.19 0.811 2033 C09 87419341 rs3211683 A 0.088 10635 9.41E−05 1.29 0.111 1700 2.86E−04 1.25 0.108 2034 C11 42877662 rs1532096 T 0.861 10635 9.63E−05 1.26 0.887 1700 9.38E−05 1.24 0.885 2034 C22 42582255 rs738407 A 0.635 10634 9.70E−05 1.18 0.672 1700 5.67E−04 1.14 0.665 2034 C17 17947855 rs3183702 T 0.349 10630 9.76E−05 1.17 0.386 1699 1.01E−03 1.13 0.378 2033 C02 39191408 rs963731 C 0.951 10365 1.01E−04 1.49 0.966 1651 1.21E−04 1.44 0.965 1978 C09 87414699 rs3211650 T 0.089 10634 1.02E−04 1.29 0.111 1700 3.09E−04 1.25 0.108 2034 C06 71671372 rs7753765 A 0.144 10633 1.03E−04 1.23 0.172 1700 2.32E−04 1.2 0.169 2034 C01 30378256 rs593993 C 0.834 10626 1.09E−04 1.24 0.862 1697 7.25E−05 1.23 0.86 2031 C11 17756131 rs7946133 T 0.915 10540 1.12E−04 1.35 0.936 1641 1.43E−04 1.31 0.934 1968 C02 212605929 rs17406681 T 0.275 10635 1.13E−04 1.18 0.31 1700 3.42E−04 1.15 0.305 2034 C02 212605929 rs17406681 T 0.275 10635 1.13E−04 1.18 0.31 1700 3.42E−04 1.15 0.305 2034 C03 14276852 rs6772823 G 0.276 10580 1.18E−04 1.18 0.31 1675 1.98E−04 1.16 0.307 2008 C17 17934326 rs9902941 C 0.349 10634 1.25E−04 1.17 0.385 1700 1.18E−03 1.13 0.377 2034 C02 123847245 rs1395930 T 0.494 10633 1.25E−04 1.16 0.532 1698 3.18E−05 1.16 0.532 2032 C05 158647626 rs254850 T 0.215 10635 1.29E−04 1.19 0.247 1700 1.30E−03 1.15 0.24 2034 C03 170405740 rs756644 A 0.431 10633 1.30E−04 1.16 0.468 1700 1.56E−03 1.12 0.459 2034 C12 47223943 rs12581026 C 0.046 10634 1.33E−04 1.39 0.063 1700 3.67E−03 1.27 0.058 2034 C17 17849989 rs4925108 C 0.392 10623 1.35E−04 1.16 0.429 1700 4.28E−04 1.14 0.424 2034 C17 17849989 rs4925108 C 0.392 10623 1.35E−04 1.16 0.429 1700 4.28E−04 1.14 0.424 2034 C12 95967869 rs11108788 G 0.032 10618 1.38E−04 1.47 0.046 1698 3.43E−04 1.4 0.044 2032 C01 53740224 rs2294512 G 0.682 10635 1.41E−04 1.18 0.716 1700 1.47E−03 1.13 0.708 2034 C05 102457857 rs9327877 T 0.19 10634 1.45E−04 1.2 0.22 1700 2.47E−04 1.18 0.217 2034 C04 21549446 rs10516402 C 0.504 10633 1.46E−04 1.16 0.541 1700 2.09E−04 1.15 0.538 2034 C04 21549446 rs10516402 C 0.504 10633 1.46E−04 1.16 0.541 1700 2.09E−04 1.15 0.538 2034 C20 15053882 rs411944 G 0.645 10632 1.47E−04 1.17 0.68 1700 1.22E−03 1.13 0.673 2033 C13 42581715 rs9525923 A 0.208 10635 1.56E−04 1.19 0.239 1700 5.62E−04 1.16 0.234 2034 C02 176947426 rs921083 G 0.776 10633 1.56E−04 1.2 0.806 1700 2.93E−04 1.18 0.803 2034 C05 97515007 rs950195 G 0.63 10631 1.65E−04 1.17 0.665 1700 5.67E−05 1.17 0.665 2034 C05 6897773 rs870347 T 0.924 10635 1.73E−04 1.35 0.942 1700 1.14E−03 1.27 0.939 2034 C14 67308303 rs8003722 A 0.102 10634 1.73E−04 1.26 0.126 1700 2.73E−04 1.23 0.123 2034 C05 50867460 rs6449708 T 0.452 10611 1.73E−04 1.16 0.489 1693 1.17E−03 1.13 0.482 2027 C05 50867460 rs6449708 T 0.452 10611 1.73E−04 1.16 0.489 1693 1.17E−03 1.13 0.482 2027 C06 160872518 rs11751605 C 0.11 10632 1.75E−04 1.25 0.134 1700 3.87E−04 1.22 0.131 2033 C02 123861662 rs2661006 T 0.493 10623 1.76E−04 1.16 0.529 1696 5.58E−05 1.16 0.529 2030 C13 45452894 rs7322927 A 0.125 10635 1.78E−04 1.24 0.151 1700 3.29E−03 1.17 0.144 2034 C05 56215087 rs832540 C 0.415 10626 1.81E−04 1.16 0.451 1700 3.23E−04 1.14 0.447 2034 C04 166320428 rs11723570 C 0.511 10635 1.92E−04 1.16 0.547 1700 1.49E−04 1.15 0.545 2034 C19 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1.16 0.528 1700 4.64E−04 1.14 0.524 2034 C07 116792948 rs213977 G 0.409 10633 2.28E−04 1.16 0.445 1700 3.73E−04 1.14 0.441 2034 C02 76346853 rs1595968 T 0.394 10622 2.29E−04 1.16 0.43 1695 1.92E−04 1.15 0.428 2029 C01 20544933 rs12724604 A 0.036 10634 2.35E−04 1.42 0.051 1700 5.31E−05 1.43 0.051 2034 C04 21483069 rs1827591 G 0.535 10635 2.41E−04 1.16 0.571 1700 2.98E−04 1.14 0.568 2034 C01 148957002 rs12066445 A 0.299 10635 2.47E−04 1.17 0.332 1700 1.08E−03 1.14 0.326 2034 C17 9590955 rs3891720 C 0.869 10613 2.47E−04 1.25 0.893 1698 4.95E−04 1.22 0.89 2032 C17 17943470 rs4925119 A 0.347 10615 2.54E−04 1.16 0.381 1696 2.24E−03 1.12 0.373 2029 C08 144065203 rs7844961 T 0.09 10635 2.61E−04 1.27 0.112 1700 1.82E−03 1.21 0.107 2034 C01 57254228 rs2991515 T 0.479 10635 2.67E−04 1.15 0.515 1700 2.39E−05 1.17 0.518 2034 C20 4150948 rs1741315 A 0.483 10633 2.68E−04 1.15 0.519 1700 5.86E−04 1.13 0.514 2034 C20 4150948 rs1741315 A 0.483 10633 2.68E−04 1.15 0.519 1700 5.86E−04 1.13 0.514 2034 C09 132592188 rs4917341 C 0.481 10587 2.69E−04 1.15 0.516 1697 1.12E−03 1.13 0.51 2029 C08 28215758 rs4732849 T 0.273 10635 2.70E−04 1.17 0.306 1700 1.05E−02 1.11 0.294 2034 C20 47199260 rs981303 A 0.929 10623 2.73E−04 1.35 0.946 1696 1.53E−05 1.4 0.948 2029 C10 84830992 rs7921473 G 0.815 10635 2.77E−04 1.21 0.842 1700 3.79E−05 1.22 0.844 2034 C15 43779321 rs11630033 C 0.9 10606 2.77E−04 1.29 0.92 1694 3.81E−04 1.26 0.918 2028 C20 13686900 rs2026058 T 0.764 10634 2.77E−04 1.19 0.794 1700 3.63E−03 1.14 0.786 2034 C21 16738666 rs1349227 T 0.238 10635 2.77E−04 1.18 0.269 1700 4.65E−04 1.16 0.266 2034 C07 116579323 rs1029396 G 0.069 10634 2.78E−04 1.3 0.088 1700 2.26E−04 1.28 0.087 2034 C11 7588325 rs12292613 T 0.892 10509 2.88E−04 1.28 0.913 1670 3.35E−03 1.2 0.908 2003 C08 70812569 rs3829049 G 0.708 10635 2.91E−04 1.17 0.74 1700 5.19E−04 1.15 0.737 2034 C03 25122677 rs6763490 C 0.6 10635 2.94E−04 1.16 0.635 1700 7.39E−04 1.14 0.63 2034 C17 17911836 rs4925114 A 0.359 10615 2.97E−04 1.16 0.393 1697 1.89E−03 1.12 0.386 2031 C01 19443039 rs7535952 A 0.717 10510 2.99E−04 1.18 0.749 1660 3.29E−03 1.13 0.741 1990 C07 46273364 rs10243723 G 0.97 10628 3.04E−04 1.61 0.981 1699 1.27E−03 1.47 0.979 2033 C08 18243855 rs7006687 T 0.575 10632 3.05E−04 1.16 0.61 1698 7.18E−05 1.16 0.61 2032 C16 61289938 rs12924635 G 0.389 10380 3.06E−04 1.16 0.425 1624 3.29E−03 1.12 0.416 1953 C04 10479642 rs4697653 G 0.526 10604 3.08E−04 1.15 0.562 1699 8.82E−04 1.13 0.556 2032 C12 112489807 rs249047 A 0.614 10634 3.11E−04 1.16 0.648 1700 3.87E−03 1.12 0.639 2034 C07 67324200 rs12540706 G 0.311 10634 3.15E−04 1.16 0.344 1700 2.70E−03 1.12 0.337 2034 C10 26191683 rs7086207 G 0.404 10625 3.17E−04 1.15 0.439 1699 5.10E−04 1.14 0.435 2033 C05 40281304 rs13165359 G 0.877 10634 3.19E−04 1.26 0.899 1700 2.77E−03 1.19 0.894 2034 C05 50777478 rs10038238 A 0.567 10634 3.20E−04 1.15 0.602 1699 1.41E−03 1.13 0.596 2033 C01 65319795 rs2025805 C 0.565 10634 3.25E−04 1.15 0.6 1700 3.31E−04 1.14 0.597 2034 C17 18204411 rs854813 C 0.387 10632 3.25E−04 1.15 0.422 1700 6.90E−04 1.13 0.417 2034 C04 21576609 rs4377576 C 0.54 10634 3.25E−04 1.15 0.575 1700 5.32E−04 1.14 0.572 2034 C04 21576609 rs4377576 C 0.54 10634 3.25E−04 1.15 0.575 1700 5.32E−04 1.14 0.572 2034 C12 65789635 rs1465026 G 0.832 10632 3.27E−04 1.22 0.858 1700 8.82E−05 1.22 0.858 2034 C18 2609280 rs4271662 C 0.58 10594 3.34E−04 1.16 0.615 1695 9.97E−04 1.13 0.61 2026 C01 150696580 rs4845552 G 0.125 10588 3.40E−04 1.23 0.149 1698 2.40E−04 1.21 0.148 2030 C15 24926452 rs2110209 A 0.047 10635 3.42E−04 1.36 0.062 1700 9.53E−04 1.3 0.06 2034 C03 170400106 rs1430435 G 0.503 10634 3.44E−04 1.15 0.538 1700 2.59E−03 1.12 0.53 2034 C06 72208904 rs182106 T 0.523 10635 3.50E−04 1.15 0.558 1700 8.17E−04 1.13 0.554 2034 C03 145877192 rs10935515 C 0.583 10623 3.51E−04 1.15 0.618 1699 6.10E−04 1.14 0.614 2033 C06 72149930 rs9360453 G 0.711 10616 3.57E−04 1.17 0.742 1697 4.11E−04 1.16 0.74 2030 C05 115427457 rs17138668 C 0.947 10634 3.60E−04 1.41 0.962 1700 1.06E−03 1.34 0.96 2034 CX 91547326 rs6615536 G 0.987 8272 3.62E−04 2.85 0.995 1103 1.19E−04 2.84 0.995 1316 C03 194770024 rs883279 C 0.905 10632 3.63E−04 1.29 0.925 1699 1.46E−04 1.29 0.925 2033 C07 116680904 rs2283054 A 0.069 10634 3.73E−04 1.3 0.087 1699 3.39E−04 1.27 0.086 2033 C06 136340016 rs9376173 A 0.629 10613 3.74E−04 1.16 0.663 1692 1.42E−03 1.13 0.657 2026 C20 4152600 rs1741318 A 0.447 10633 3.75E−04 1.15 0.482 1700 1.07E−03 1.13 0.477 2034 C20 4152600 rs1741318 A 0.447 10633 3.75E−04 1.15 0.482 1700 1.07E−03 1.13 0.477 2034 C12 47206273 rs12425518 A 0.043 10611 3.78E−04 1.37 0.058 1697 9.36E−03 1.25 0.053 2029 C10 8196155 rs541045 C 0.431 10501 3.79E−04 1.15 0.466 1659 1.79E−03 1.12 0.459 1992 C01 20789662 rs12741305 C 0.036 10635 3.85E−04 1.4 0.05 1698 1.09E−04 1.41 0.05 2031 C07 116688223 rs2237721 C 0.069 10634 3.85E−04 1.29 0.087 1700 3.50E−04 1.27 0.086 2034 C08 5498753 rs10503316 C 0.776 10635 3.87E−04 1.19 0.804 1700 2.83E−03 1.14 0.798 2034 C05 119516035 rs7721883 T 0.461 10597 3.89E−04 1.15 0.496 1698 7.26E−03 1.1 0.486 2032 C02 135122883 rs2139311 C 0.594 10622 3.90E−04 1.15 0.628 1699 3.72E−04 1.14 0.626 2033 C01 113676295 rs2476601 A 0.13 10633 3.93E−04 1.22 0.154 1700 2.39E−04 1.21 0.153 2034 C18 53271813 rs634285 G 0.913 10634 3.98E−04 1.3 0.931 1700 3.28E−03 1.22 0.927 2034 C14 99695081 rs17776453 G 0.951 10633 4.00E−04 1.43 0.966 1699 2.30E−04 1.41 0.965 2033 C05 56242295 rs252890 A 0.425 10632 4.02E−04 1.15 0.459 1699 5.18E−04 1.14 0.456 2033 C01 40523163 rs7520394 T 0.651 10619 4.13E−04 1.16 0.684 1698 6.36E−03 1.11 0.674 2032 C22 44896799 rs739164 A 0.894 10523 4.21E−04 1.28 0.915 1645 5.43E−04 1.25 0.913 1978 C10 90674890 rs2243548 A 0.509 10625 4.25E−04 1.15 0.544 1698 5.06E−03 1.11 0.534 2031 C10 90674890 rs2243548 A 0.509 10625 4.25E−04 1.15 0.544 1698 5.06E−03 1.11 0.534 2031 CX 108301033 rs3788769 C 0.445 8210 4.25E−04 1.19 0.487 1095 1.26E−03 1.16 0.481 1307 C22 34873996 rs7364143 T 0.28 10592 4.25E−04 1.16 0.311 1696 6.90E−04 1.15 0.308 2030 C03 191533619 rs9864293 C 0.385 10632 4.43E−04 1.15 0.419 1700 9.88E−04 1.13 0.415 2033 C07 102617539 rs2270019 G 0.165 10614 4.44E−04 1.2 0.192 1697 2.59E−04 1.19 0.191 2031 C20 15229479 rs6034134 G 0.594 10634 4.48E−04 1.15 0.628 1700 1.86E−03 1.12 0.622 2034 C05 153269681 rs1461236 T 0.855 10614 4.49E−04 1.23 0.879 1689 4.26E−03 1.17 0.873 2023 C11 92904904 rs2658801 A 0.269 10634 4.49E−04 1.16 0.3 1700 1.76E−04 1.16 0.299 2034 C17 10435400 rs9903582 C 0.745 10634 4.53E−04 1.18 0.775 1700 1.92E−03 1.14 0.769 2034 C15 84295353 rs4887480 G 0.769 10629 4.55E−04 1.18 0.798 1700 3.82E−03 1.14 0.791 2034 C17 17860913 rs752579 G 0.388 10632 4.57E−04 1.15 0.421 1700 1.55E−03 1.12 0.416 2034 C17 17860913 rs752579 G 0.388 10632 4.57E−04 1.15 0.421 1700 1.55E−03 1.12 0.416 2034 C14 92765567 rs10498639 A 0.423 10633 4.57E−04 1.15 0.457 1700 1.35E−03 1.12 0.452 2034 C20 284362 rs723477 T 0.74 10613 4.57E−04 1.18 0.77 1694 2.16E−03 1.14 0.764 2027 C05 10009076 rs16883905 T 0.111 10635 4.59E−04 1.23 0.134 1700 7.81E−04 1.21 0.131 2034 C06 106193116 rs845851 A 0.766 10631 4.60E−04 1.18 0.794 1700 2.14E−03 1.14 0.789 2034 C08 143178480 rs9644545 T 0.476 10632 4.61E−04 1.15 0.511 1700 4.98E−03 1.11 0.502 2034 C12 9180220 rs2160424 G 0.557 10608 4.62E−04 1.15 0.591 1690 4.58E−03 1.11 0.583 2022 C12 19360345 rs10743315 G 0.878 10613 4.84E−04 1.25 0.9 1694 1.58E−03 1.2 0.896 2028 C05 56298431 rs2408654 C 0.273 10635 4.84E−04 1.16 0.304 1700 4.74E−04 1.15 0.302 2034 C05 167473287 rs7705176 G 0.781 10635 4.87E−04 1.19 0.809 1700 1.68E−03 1.15 0.805 2034 C03 62396924 rs1997366 C 0.792 10623 4.88E−04 1.19 0.82 1700 9.05E−04 1.17 0.817 2033 C03 62396924 rs1997366 C 0.792 10623 4.88E−04 1.19 0.82 1700 9.05E−04 1.17 0.817 2033 C04 21494114 rs6448072 C 0.655 10634 4.89E−04 1.16 0.688 1700 1.95E−04 1.16 0.687 2034 C20 49593462 rs913673 C 0.539 10624 4.90E−04 1.15 0.574 1700 1.89E−03 1.12 0.568 2034 C10 119318254 rs1557227 C 0.855 10635 4.91E−04 1.23 0.879 1700 4.19E−04 1.21 0.877 2034 C05 158541049 rs270661 A 0.205 10634 4.93E−04 1.18 0.233 1699 3.06E−03 1.14 0.227 2033 C05 158541049 rs270661 A 0.205 10634 4.93E−04 1.18 0.233 1699 3.06E−03 1.14 0.227 2033 C06 72209498 rs199623 A 0.523 10635 4.98E−04 1.15 0.557 1700 1.17E−03 1.13 0.552 2034 C09 134953713 rs2385891 A 0.544 10612 4.98E−04 1.15 0.578 1694 2.79E−03 1.12 0.571 2028 C09 16321304 rs9407756 G 0.67 10634 5.13E−04 1.16 0.702 1700 3.35E−03 1.12 0.695 2034 C08 1315247 rs7386449 A 0.68 10634 5.29E−04 1.16 0.711 1700 7.10E−04 1.14 0.708 2034 C08 1315247 rs7386449 A 0.68 10634 5.29E−04 1.16 0.711 1700 7.10E−04 1.14 0.708 2034 C05 178690232 rs3756566 G 0.401 10632 5.32E−04 1.15 0.434 1700 3.57E−04 1.14 0.433 2034 C10 84919047 rs11198993 A 0.688 10564 5.37E−04 1.16 0.719 1692 1.05E−05 1.19 0.725 2024 C12 65801361 rs1526839 G 0.831 10632 5.39E−04 1.21 0.856 1700 1.32E−04 1.21 0.856 2034 C18 58503179 rs12458349 G 0.061 10603 5.50E−04 1.3 0.078 1700 1.46E−04 1.31 0.078 2032 C06 106204603 rs4946680 T 0.632 10635 5.50E−04 1.15 0.665 1700 1.76E−03 1.13 0.66 2034 C03 124473843 rs9847700 G 0.852 10529 5.53E−04 1.23 0.876 1654 9.60E−04 1.2 0.873 1986 C18 56405620 rs603119 T 0.386 10606 5.54E−04 1.15 0.419 1699 9.25E−05 1.16 0.421 2032 C06 113938753 rs4945955 T 0.092 10614 5.55E−04 1.25 0.112 1697 5.18E−04 1.23 0.111 2031 C05 26932085 rs1382932 C 0.68 10635 5.60E−04 1.16 0.711 1700 1.13E−03 1.14 0.707 2034 C05 76583322 rs974280 G 0.357 10635 5.63E−04 1.15 0.39 1700 1.34E−03 1.13 0.385 2034 C16 19044749 rs7500550 G 0.774 10635 5.63E−04 1.18 0.802 1699 1.97E−03 1.15 0.798 2033 C05 56284090 rs1445998 A 0.4 10635 5.67E−04 1.15 0.433 1700 5.78E−04 1.14 0.43 2034 C14 48189298 rs4898630 A 0.876 10633 5.71E−04 1.24 0.898 1700 9.58E−04 1.21 0.895 2034 C19 34828875 rs4805463 G 0.906 10634 5.72E−04 1.28 0.925 1700 1.08E−03 1.24 0.923 2034 C07 28352068 rs1976489 G 0.249 10635 5.77E−04 1.17 0.279 1700 2.15E−03 1.14 0.274 2034 C12 19263624 rs9805106 G 0.817 10618 5.79E−04 1.2 0.843 1695 7.98E−04 1.18 0.84 2029 C17 17915667 rs11868035 A 0.296 10623 5.79E−04 1.16 0.327 1699 5.61E−03 1.12 0.319 2033 C17 17915667 rs11868035 A 0.296 10623 5.79E−04 1.16 0.327 1699 5.61E−03 1.12 0.319 2033 C01 209613176 rs792446 G 0.611 10634 5.80E−04 1.15 0.644 1700 1.30E−02 1.1 0.633 2033 C13 109862872 rs1163852 C 0.714 10635 5.83E−04 1.17 0.744 1700 2.89E−04 1.16 0.743 2034 C03 22619885 rs1870480 G 0.38 10635 5.85E−04 1.15 0.413 1700 3.12E−04 1.14 0.412 2034 C15 97226804 rs2684790 T 0.146 10634 5.87E−04 1.2 0.17 1700 7.79E−04 1.18 0.168 2034 C14 44542892 rs1742655 C 0.884 10635 5.91E−04 1.25 0.905 1700 3.42E−03 1.19 0.901 2034 C12 114213023 rs1920947 C 0.812 10635 5.92E−04 1.2 0.838 1700 7.20E−03 1.14 0.831 2034 C01 30387821 rs12029866 G 0.771 10634 5.93E−04 1.18 0.799 1700 1.33E−04 1.19 0.8 2034 C11 91095458 rs2568712 T 0.385 10599 5.98E−04 1.15 0.418 1699 1.68E−03 1.12 0.413 2031 C01 168129978 rs11582943 A 0.94 10619 5.99E−04 1.36 0.955 1693 6.87E−04 1.33 0.954 2027 C01 168129978 rs11582943 A 0.94 10619 5.99E−04 1.36 0.955 1693 6.87E−04 1.33 0.954 2027 C02 49219942 rs3788982 G 0.871 10635 6.02E−04 1.24 0.893 1700 8.11E−05 1.25 0.894 2034 C10 131670000 rs639079 G 0.187 10389 6.03E−04 1.18 0.214 1664 7.05E−04 1.17 0.212 1992 C01 76636957 rs1566250 G 0.702 10634 6.13E−04 1.16 0.732 1700 1.98E−04 1.16 0.733 2034 C12 87964674 rs1401875 T 0.057 10626 6.13E−04 1.31 0.073 1697 1.83E−03 1.26 0.07 2031 C12 87964674 rs1401875 T 0.057 10626 6.13E−04 1.31 0.073 1697 1.83E−03 1.26 0.07 2031 C05 158753477 rs953861 G 0.16 10632 6.14E−04 1.19 0.185 1700 1.51E−02 1.13 0.176 2034 C01 82599958 rs12032817 G 0.371 10635 6.15E−04 1.15 0.404 1700 6.29E−03 1.11 0.396 2034 C03 78544480 rs2055707 A 0.418 10603 6.20E−04 1.15 0.451 1699 2.42E−03 1.12 0.445 2033 C19 4231186 rs10419363 T 0.299 10610 6.22E−04 1.16 0.331 1695 8.39E−04 1.14 0.328 2028 C02 235330231 rs12617590 C 0.199 10624 6.29E−04 1.18 0.227 1700 2.26E−03 1.15 0.222 2034 C04 87398087 rs2589506 G 0.451 10632 6.31E−04 1.14 0.485 1700 1.15E−04 1.15 0.486 2034 C10 87792858 rs3814614 T 0.501 10628 6.35E−04 1.14 0.535 1700 1.05E−03 1.13 0.531 2034 C04 97290133 rs10516987 G 0.797 10598 6.35E−04 1.19 0.824 1691 1.55E−03 1.16 0.82 2023 C13 101108783 rs1375719 C 0.499 10634 6.36E−04 1.14 0.532 1700 1.03E−02 1.1 0.522 2034 C17 18231090 rs854793 A 0.202 10631 6.36E−04 1.18 0.229 1700 1.59E−03 1.15 0.225 2034 C15 76722261 rs11072793 G 0.227 10613 6.38E−04 1.17 0.255 1695 1.52E−03 1.14 0.251 2029 C09 8437732 rs2890795 T 0.577 10630 6.38E−04 1.15 0.61 1700 1.20E−03 1.13 0.606 2034 C07 67296404 rs4527771 A 0.406 10572 6.43E−04 1.15 0.439 1694 8.45E−03 1.1 0.43 2027 C13 66843127 rs17070671 T 0.833 10633 6.44E−04 1.21 0.857 1700 9.00E−03 1.14 0.85 2034 C16 73542120 rs1038864 C 0.183 10634 6.45E−04 1.18 0.209 1700 4.45E−03 1.14 0.203 2034 C06 25536933 rs722086 T 0.856 10166 6.47E−04 1.22 0.879 1687 7.47E−03 1.16 0.873 2015 C08 70811871 rs4738034 C 0.701 10635 6.49E−04 1.16 0.731 1700 9.61E−04 1.14 0.728 2034 C18 55095560 rs657773 C 0.551 10634 6.57E−04 1.15 0.585 1700 1.04E−03 1.13 0.581 2034 C02 134844429 rs2321299 C 0.568 10633 6.58E−04 1.15 0.601 1700 3.50E−03 1.11 0.595 2033 C06 149543409 rs6570956 T 0.734 10635 6.61E−04 1.17 0.764 1700 6.82E−03 1.12 0.756 2034 C12 116667030 rs4767629 T 0.139 10634 6.61E−04 1.2 0.163 1700 5.33E−03 1.15 0.157 2034 C01 80891035 rs1030414 G 0.901 10635 6.73E−04 1.27 0.92 1700 3.45E−04 1.26 0.92 2033 C06 69176005 rs1565487 A 0.856 10630 6.74E−04 1.22 0.879 1700 2.07E−04 1.22 0.879 2034 C10 123913719 rs2239586 T 0.118 10630 6.75E−04 1.22 0.14 1700 2.95E−03 1.18 0.136 2034 C11 122290366 rs4936757 C 0.565 10633 6.76E−04 1.15 0.598 1700 3.91E−03 1.11 0.591 2034 C12 22090132 rs2955503 A 0.654 10629 6.82E−04 1.15 0.686 1700 2.41E−04 1.15 0.686 2033 C17 52089014 rs11656018 C 0.703 10600 6.84E−04 1.16 0.733 1699 8.06E−04 1.15 0.731 2032 C06 159976575 rs2758317 C 0.427 10572 6.86E−04 1.14 0.46 1690 6.67E−03 1.11 0.452 2019 C18 43266738 rs17734724 G 0.271 10635 6.87E−04 1.16 0.301 1700 3.27E−03 1.13 0.295 2034 C02 19979982 rs12467812 G 0.331 10634 6.88E−04 1.15 0.363 1700 2.30E−04 1.15 0.363 2034 C15 51085506 rs1156234 G 0.791 10633 6.91E−04 1.18 0.818 1700 5.59E−04 1.17 0.816 2034 C10 123156230 rs2936875 T 0.782 10629 6.92E−04 1.18 0.809 1699 4.42E−03 1.14 0.803 2033 C19 58638423 rs11668495 C 0.944 10470 7.08E−04 1.38 0.959 1668 1.43E−03 1.32 0.957 1995 C07 136198861 rs11761344 T 0.116 10635 7.12E−04 1.22 0.138 1699 8.84E−04 1.2 0.136 2033 C10 84739213 rs4617529 G 0.852 10635 7.15E−04 1.22 0.875 1700 6.68E−04 1.2 0.873 2034 C08 139196618 rs4909761 T 0.262 10634 7.20E−04 1.16 0.291 1700 2.65E−03 1.13 0.286 2034 C05 94602573 rs6556861 G 0.567 10634 7.24E−04 1.14 0.6 1700 2.99E−03 1.12 0.594 2034 C09 132606652 rs1930788 C 0.247 10635 7.27E−04 1.16 0.276 1700 4.10E−03 1.13 0.27 2034 C05 157926810 rs2964513 A 0.689 10559 7.29E−04 1.16 0.72 1698 3.01E−03 1.13 0.714 2030 C08 5508780 rs6991017 T 0.794 10607 7.30E−04 1.19 0.82 1698 5.36E−03 1.14 0.814 2032 C02 135133800 rs12473666 T 0.137 10629 7.31E−04 1.2 0.16 1700 2.94E−03 1.17 0.156 2034 C17 18149041 rs2955355 C 0.287 10635 7.35E−04 1.16 0.317 1700 3.19E−03 1.12 0.311 2034 C11 44349237 rs10838271 C 0.21 10635 7.42E−04 1.17 0.238 1700 3.32E−03 1.14 0.233 2034 C01 238617451 rs1341449 A 0.545 10559 7.44E−04 1.14 0.579 1681 1.15E−03 1.13 0.575 2014 C15 34765965 rs1901725 T 0.125 10635 7.47E−04 1.21 0.148 1700 3.63E−03 1.17 0.143 2034 C10 87786571 rs4933391 A 0.386 10634 7.50E−04 1.14 0.418 1700 1.30E−03 1.13 0.414 2034 C01 80911800 rs7531507 G 0.921 10634 7.52E−04 1.3 0.938 1700 3.18E−04 1.3 0.938 2034 C14 57289229 rs2069334 A 0.184 10635 7.54E−04 1.18 0.211 1700 6.14E−03 1.13 0.204 2034 C02 17299060 rs2342551 T 0.713 10635 7.54E−04 1.16 0.743 1700 1.23E−03 1.14 0.74 2034 C02 128492107 rs2244871 C 0.41 10632 7.62E−04 1.14 0.442 1700 7.38E−04 1.13 0.44 2034 C16 75061517 rs1862737 C 0.481 10635 7.67E−04 1.14 0.514 1700 1.75E−03 1.12 0.51 2034 C04 129868334 rs7690289 T 0.63 10596 7.70E−04 1.15 0.661 1697 7.24E−04 1.14 0.659 2031 C04 129868334 rs7690289 T 0.63 10596 7.70E−04 1.15 0.661 1697 7.24E−04 1.14 0.659 2031 C18 73086657 rs2156643 G 0.41 10631 7.70E−04 1.14 0.443 1700 1.49E−03 1.12 0.439 2034 C11 7440298 rs11041390 A 0.729 10635 7.70E−04 1.16 0.758 1700 8.75E−03 1.12 0.75 2034 C15 34765482 rs7183966 G 0.125 10632 7.75E−04 1.21 0.148 1698 3.73E−03 1.17 0.143 2032 C09 28114180 rs1452336 A 0.495 10608 7.76E−04 1.14 0.529 1695 1.89E−04 1.15 0.53 2029 C05 102480237 rs34374 A 0.671 10635 7.80E−04 1.15 0.702 1699 5.86E−03 1.11 0.695 2033 C05 82104191 rs6452479 C 0.934 10595 7.88E−04 1.33 0.95 1695 6.46E−04 1.31 0.949 2028 C18 73085584 rs2850889 C 0.41 10634 7.91E−04 1.14 0.443 1700 1.53E−03 1.12 0.439 2034 C11 20014579 rs920675 A 0.358 10635 7.95E−04 1.15 0.39 1700 5.37E−04 1.14 0.389 2034 C03 39292564 rs2853705 T 0.209 10634 7.97E−04 1.17 0.236 1700 2.79E−03 1.14 0.231 2034 C18 73086818 rs2850892 C 0.41 10631 7.98E−04 1.14 0.443 1700 1.55E−03 1.12 0.439 2034 C04 178149338 rs309770 G 0.889 10635 8.01E−04 1.25 0.909 1700 5.03E−04 1.24 0.908 2034 C11 7444767 rs7113222 G 0.739 10632 8.03E−04 1.17 0.768 1700 1.29E−02 1.11 0.759 2034 C03 6735499 rs7638636 A 0.494 10231 8.03E−04 1.14 0.528 1648 5.59E−04 1.14 0.526 1972 C02 42489923 rs10202624 A 0.094 10634 8.15E−04 1.24 0.114 1700 1.79E−04 1.25 0.114 2034 C06 20707867 rs2294809 G 0.799 10626 8.19E−04 1.19 0.825 1699 3.18E−03 1.15 0.82 2033 C02 118487620 rs2245113 A 0.174 10632 8.20E−04 1.18 0.199 1700 1.79E−02 1.12 0.191 2034 C19 17024661 rs2305758 G 0.684 10633 8.21E−04 1.16 0.714 1700 4.38E−04 1.15 0.714 2034 C19 17024661 rs2305758 G 0.684 10633 8.21E−04 1.16 0.714 1700 4.38E−04 1.15 0.714 2034 C01 63908878 rs1747924 T 0.808 10622 8.23E−04 1.19 0.834 1700 9.80E−03 1.13 0.827 2034 C22 34883676 rs5995259 A 0.337 10635 8.26E−04 1.15 0.369 1700 2.83E−03 1.12 0.363 2034 C02 45292999 rs908571 C 0.291 10635 8.27E−04 1.15 0.321 1699 1.62E−03 1.13 0.318 2033 C20 33195666 rs734484 C 0.709 10635 8.29E−04 1.16 0.738 1699 2.20E−03 1.13 0.734 2033 C16 2009168 rs8057913 C 0.264 10634 8.39E−04 1.16 0.293 1700 1.13E−03 1.14 0.29 2034 C03 99699602 rs3796139 G 0.145 10476 8.40E−04 1.2 0.169 1685 4.25E−03 1.16 0.164 2011 C02 135194839 rs1257208 A 0.138 10633 8.41E−04 1.2 0.161 1700 1.98E−03 1.17 0.158 2034 C20 5928108 rs236110 G 0.87 10635 8.43E−04 1.23 0.892 1698 9.17E−04 1.21 0.89 2031 C05 3644654 rs710998 T 0.899 10630 8.55E−04 1.26 0.918 1699 1.20E−03 1.23 0.917 2033 C02 49398605 rs6743414 G 0.847 10634 8.62E−04 1.21 0.87 1700 1.51E−04 1.22 0.871 2034 C13 38516680 rs9315759 C 0.13 10635 8.63E−04 1.21 0.152 1700 3.14E−03 1.17 0.148 2034 C01 184657396 rs4651384 G 0.687 10634 8.72E−04 1.15 0.717 1700 4.41E−03 1.12 0.711 2034 C19 17031885 rs12459084 T 0.351 10633 8.76E−04 1.15 0.382 1700 3.24E−03 1.12 0.376 2034 C17 48847103 rs4794128 A 0.272 10634 8.77E−04 1.16 0.302 1700 1.05E−03 1.14 0.299 2034 C08 32544721 rs12547858 T 0.195 10624 8.80E−04 1.17 0.221 1700 7.59E−04 1.16 0.22 2034 C09 16318137 rs4961695 C 0.803 10614 8.81E−04 1.19 0.829 1697 1.23E−03 1.17 0.826 2029 C02 170296713 rs2268365 G 0.125 10635 8.83E−04 1.21 0.147 1698 2.14E−03 1.18 0.144 2032 C02 170296713 rs2268365 G 0.125 10635 8.83E−04 1.21 0.147 1698 2.14E−03 1.18 0.144 2032 C07 17752626 rs4470902 C 0.417 10634 8.84E−04 1.14 0.45 1700 8.58E−04 1.13 0.447 2034 C14 57303694 rs17095237 G 0.16 10634 8.85E−04 1.19 0.185 1700 6.54E−03 1.14 0.179 2034 C05 38969280 rs357291 C 0.395 10579 8.89E−04 1.14 0.428 1688 6.20E−03 1.11 0.42 2020 C06 30109076 rs166327 A 0.601 10634 8.91E−04 1.14 0.633 1700 4.98E−03 1.11 0.626 2034 C03 125374402 rs6438839 A 0.077 10632 8.92E−04 1.26 0.095 1700 4.40E−04 1.25 0.095 2034 C05 153231957 rs1870739 C 0.855 10629 8.92E−04 1.21 0.877 1697 6.74E−03 1.16 0.872 2031 C01 40507124 rs661221 G 0.803 10614 8.92E−04 1.19 0.828 1697 8.83E−03 1.13 0.821 2030 C05 50944695 rs4865673 G 0.643 10635 8.94E−04 1.15 0.674 1700 1.99E−03 1.13 0.67 2034 C03 186444329 rs6803944 C 0.841 10635 8.95E−04 1.21 0.865 1700 7.54E−04 1.19 0.863 2034 C05 102439618 rs26434 T 0.704 10617 8.95E−04 1.16 0.734 1697 5.12E−03 1.12 0.727 2031 C10 29327574 rs788053 T 0.747 10635 9.01E−04 1.17 0.775 1700 1.80E−03 1.14 0.771 2034 C12 101671864 rs12311520 C 0.867 10624 9.12E−04 1.22 0.889 1700 5.86E−03 1.17 0.884 2033 C01 29565842 rs1932397 G 0.821 10635 9.14E−04 1.19 0.845 1700 2.07E−03 1.16 0.842 2034 C04 10653042 rs959233 G 0.445 10622 9.20E−04 1.14 0.477 1700 1.23E−03 1.13 0.474 2033 C08 144018676 rs5297 C 0.09 10632 9.22E−04 1.24 0.109 1700 4.01E−03 1.19 0.105 2034 C08 143110958 rs747551 T 0.436 10633 9.27E−04 1.14 0.469 1700 1.39E−03 1.12 0.465 2034 C18 55790697 rs8082768 T 0.18 10621 9.28E−04 1.18 0.206 1700 1.97E−04 1.19 0.207 2034 C12 111537264 rs1015249 C 0.689 10635 9.36E−04 1.15 0.719 1700 1.59E−03 1.13 0.715 2034 C08 59026980 rs7010934 C 0.842 10632 9.45E−04 1.2 0.865 1700 2.40E−03 1.17 0.862 2034 C01 78361370 rs1412414 G 0.621 10634 9.53E−04 1.15 0.652 1699 5.85E−03 1.11 0.645 2033 C06 165543591 rs1744503 T 0.478 10631 9.57E−04 1.14 0.511 1700 2.74E−04 1.14 0.512 2033 C01 76521831 rs10518531 C 0.842 10561 9.57E−04 1.21 0.865 1668 3.57E−04 1.21 0.865 1998 C12 119365986 rs719450 C 0.918 10635 9.57E−04 1.29 0.935 1700 2.69E−04 1.3 0.935 2034 C12 119365986 rs719450 C 0.918 10635 9.57E−04 1.29 0.935 1700 2.69E−04 1.3 0.935 2034 C03 175246538 rs1421420 A 0.725 10633 9.62E−04 1.16 0.754 1700 2.21E−02 1.1 0.743 2034 C06 29542163 rs2107191 G 0.439 10634 9.63E−04 1.14 0.471 1700 4.51E−03 1.11 0.465 2034 C06 29542163 rs2107191 G 0.439 10634 9.63E−04 1.14 0.471 1700 4.51E−03 1.11 0.465 2034 C05 76806011 rs3816609 A 0.356 10632 9.64E−04 1.14 0.387 1700 2.31E−03 1.12 0.382 2034 C18 56570151 rs2332026 A 0.499 10634 9.72E−04 1.14 0.532 1700 1.79E−03 1.12 0.528 2034 C17 68940662 rs312750 C 0.547 10633 9.72E−04 1.14 0.579 1700 7.18E−03 1.1 0.572 2034 C03 72792674 rs2208 A 0.265 10634 9.76E−04 1.16 0.294 1700 4.77E−03 1.12 0.288 2034 C03 72733647 rs7632726 T 0.307 10635 9.77E−04 1.15 0.337 1700 3.48E−03 1.12 0.332 2034 C03 145911459 rs4401402 T 0.583 10633 9.79E−04 1.14 0.615 1700 1.80E−03 1.12 0.611 2034 C04 30752184 rs4132132 G 0.439 10618 9.80E−04 1.14 0.471 1696 7.47E−04 1.13 0.47 2030 C01 88967295 rs10801705 A 0.456 10635 9.80E−04 1.14 0.489 1699 8.76E−04 1.13 0.487 2033 C10 23151213 rs2935689 C 0.837 10635 9.81E−04 1.2 0.86 1700 6.25E−03 1.15 0.855 2034 C18 39875310 rs1015735 C 0.262 10605 9.82E−04 1.16 0.291 1695 2.57E−03 1.13 0.286 2029 C04 82259686 rs10026644 G 0.926 10619 9.83E−04 1.3 0.942 1697 4.26E−03 1.23 0.939 2028 C20 4111436 rs1741285 G 0.56 10634 9.88E−04 1.14 0.592 1698 1.72E−03 1.12 0.588 2032 C20 4111436 rs1741285 G 0.56 10634 9.88E−04 1.14 0.592 1698 1.72E−03 1.12 0.588 2032 C14 47963078 rs8007161 T 0.884 10602 9.90E−04 1.24 0.904 1698 1.63E−03 1.21 0.901 2030 C14 57288897 rs392030 G 0.635 10635 9.98E−04 1.15 0.666 1700 2.27E−03 1.12 0.661 2034 C01 19432522 rs7523192 T 0.809 10634 1.01E−03 1.19 0.834 1700 2.17E−02 1.12 0.826 2034 C08 144284828 rs4977114 C 0.026 10635 1.01E−03 1.44 0.037 1700 7.98E−04 1.42 0.036 2034 CX 4923358 rs1919026 C 0.189 8271 1.02E−03 1.22 0.221 1103 4.66E−03 1.17 0.214 1316 C01 18207864 rs2946534 T 0.572 10631 1.03E−03 1.14 0.604 1700 7.54E−04 1.13 0.602 2034 C09 28116482 rs1452337 G 0.798 10568 1.03E−03 1.18 0.824 1687 1.01E−03 1.17 0.822 2021 C19 17039119 rs7254154 C 0.351 10617 1.03E−03 1.14 0.383 1695 3.90E−03 1.12 0.377 2029 C19 17039119 rs7254154 C 0.351 10617 1.03E−03 1.14 0.383 1695 3.90E−03 1.12 0.377 2029 C08 73727022 rs1837544 G 0.24 10634 1.03E−03 1.16 0.268 1700 2.02E−03 1.14 0.264 2034 C02 183500703 rs1946815 G 0.216 10634 1.03E−03 1.17 0.243 1700 2.25E−03 1.14 0.239 2034 C07 102702234 rs17152161 C 0.159 10633 1.03E−03 1.19 0.183 1700 5.79E−03 1.14 0.177 2034 C02 216388367 rs13417729 C 0.713 10635 1.04E−03 1.16 0.742 1700 1.20E−03 1.14 0.74 2034 C20 13933789 rs6079235 C 0.735 10635 1.04E−03 1.16 0.763 1700 1.05E−02 1.11 0.755 2034 C04 8425936 rs3756193 G 0.46 10623 1.05E−03 1.14 0.492 1699 2.26E−03 1.12 0.488 2033 C05 76635083 rs4704400 T 0.496 10628 1.06E−03 1.14 0.528 1699 3.23E−03 1.11 0.523 2033 C17 17897321 rs11649804 A 0.292 10506 1.06E−03 1.15 0.322 1650 7.96E−03 1.11 0.315 1979 C17 17897321 rs11649804 A 0.292 10506 1.06E−03 1.15 0.322 1650 7.96E−03 1.11 0.315 1979 C14 64588026 rs17754686 A 0.306 10606 1.06E−03 1.15 0.336 1698 1.49E−03 1.13 0.333 2032 C16 2013121 rs8045288 T 0.266 10618 1.06E−03 1.15 0.295 1700 1.23E−03 1.14 0.293 2034 C04 139047812 rs10028163 G 0.202 10634 1.06E−03 1.17 0.229 1700 4.06E−04 1.17 0.229 2034 C14 98131730 rs7158073 T 0.429 10592 1.06E−03 1.14 0.461 1696 2.61E−03 1.12 0.457 2029 C07 42943442 rs3757564 C 0.069 10624 1.07E−03 1.27 0.085 1696 1.02E−03 1.25 0.084 2029 C11 110045689 rs11604632 A 0.173 10632 1.07E−03 1.18 0.198 1700 4.90E−04 1.18 0.197 2032 C17 17862368 rs4925109 A 0.317 10634 1.07E−03 1.15 0.348 1700 3.75E−03 1.12 0.342 2034 C17 17862368 rs4925109 A 0.317 10634 1.07E−03 1.15 0.348 1700 3.75E−03 1.12 0.342 2034 C12 96888528 rs7135604 A 0.652 10635 1.07E−03 1.15 0.682 1699 2.11E−02 1.09 0.672 2033 C11 97095503 rs1039953 C 0.68 10635 1.08E−03 1.15 0.71 1700 1.67E−03 1.13 0.706 2034 C04 163985671 rs9991428 G 0.96 10613 1.08E−03 1.44 0.972 1699 3.03E−03 1.35 0.97 2033 C01 148995481 rs9826 G 0.326 10553 1.09E−03 1.15 0.357 1687 5.76E−03 1.11 0.35 2016 C15 90440532 rs6496899 C 0.763 10468 1.09E−03 1.17 0.79 1684 1.08E−03 1.16 0.788 2015 C17 70257535 rs9911654 T 0.894 10635 1.09E−03 1.25 0.913 1700 2.81E−02 1.14 0.906 2034 C06 104259812 rs9373729 G 0.355 10623 1.09E−03 1.14 0.386 1698 2.92E−03 1.12 0.381 2032 C05 102509625 rs34813 G 0.709 10635 1.11E−03 1.16 0.738 1700 8.32E−03 1.11 0.731 2034 C11 134184293 rs1289450 A 0.196 10629 1.11E−03 1.17 0.222 1699 5.54E−04 1.17 0.221 2033 C12 69318052 rs2584019 T 0.89 10635 1.11E−03 1.24 0.909 1700 2.22E−04 1.26 0.91 2034 C12 69318052 rs2584019 T 0.89 10635 1.11E−03 1.24 0.909 1700 2.22E−04 1.26 0.91 2034 C08 79248604 rs2369121 T 0.72 10633 1.11E−03 1.16 0.749 1700 8.70E−04 1.15 0.747 2034 C07 23296885 rs1542608 G 0.192 10634 1.11E−03 1.17 0.218 1700 1.53E−03 1.15 0.215 2034 C10 15456765 rs1925819 T 0.558 10635 1.11E−03 1.14 0.59 1700 1.40E−02 1.09 0.58 2034 C18 3294629 rs1791098 C 0.761 10634 1.11E−03 1.17 0.788 1700 1.78E−03 1.15 0.785 2034 C07 150001841 rs11762978 A 0.654 10634 1.11E−03 1.15 0.684 1700 8.03E−03 1.11 0.677 2034 C02 209032070 rs6435401 A 0.334 10625 1.13E−03 1.14 0.365 1699 3.65E−03 1.12 0.359 2033 C02 85444821 rs11675205 A 0.254 10635 1.13E−03 1.16 0.283 1700 1.59E−03 1.14 0.28 2034 C05 158546004 rs270654 G 0.133 10635 1.13E−03 1.2 0.156 1700 3.21E−03 1.17 0.152 2034 C05 158546004 rs270654 G 0.133 10635 1.13E−03 1.2 0.156 1700 3.21E−03 1.17 0.152 2034 CX 40429441 rs3013140 G 0.931 8271 1.14E−03 1.4 0.95 1103 8.63E−04 1.38 0.949 1316 C10 78560604 rs697171 G 0.91 10620 1.14E−03 1.27 0.928 1697 1.04E−02 1.19 0.923 2030 C04 134880774 rs4864193 C 0.959 10626 1.14E−03 1.43 0.971 1700 1.87E−04 1.42 0.971 2034 C12 119366443 rs3742049 C 0.918 10622 1.14E−03 1.28 0.935 1699 3.44E−04 1.29 0.936 2033 C22 32544493 rs2267296 G 0.444 10634 1.15E−03 1.14 0.476 1700 2.30E−03 1.12 0.472 2034 C12 9208670 rs3782677 C 0.548 10635 1.15E−03 1.14 0.579 1700 8.35E−03 1.1 0.572 2034 C18 39882041 rs4340393 T 0.261 10635 1.15E−03 1.15 0.289 1700 2.80E−03 1.13 0.285 2034 C06 162239920 rs875785 C 0.916 10613 1.15E−03 1.28 0.933 1697 3.18E−04 1.29 0.934 2031 C05 102428250 rs3776859 T 0.709 10634 1.15E−03 1.15 0.738 1700 8.34E−03 1.11 0.731 2034 C17 72288299 rs191227 A 0.572 10632 1.15E−03 1.14 0.604 1700 6.91E−04 1.13 0.603 2033 C07 38886642 rs11763728 T 0.332 10635 1.15E−03 1.14 0.363 1700 1.57E−03 1.13 0.36 2034 C05 157527972 rs716376 G 0.182 10635 1.16E−03 1.17 0.208 1700 4.51E−03 1.14 0.203 2034 C06 156331097 rs4512236 T 0.418 10634 1.17E−03 1.14 0.45 1700 9.53E−04 1.13 0.448 2034 C12 111845540 rs1293758 A 0.407 10633 1.17E−03 1.14 0.439 1700 6.83E−04 1.13 0.438 2034 C08 32600898 rs10503927 T 0.471 10635 1.17E−03 1.14 0.503 1700 2.49E−03 1.12 0.498 2034 C03 175270719 rs2111956 G 0.758 10633 1.17E−03 1.17 0.785 1700 3.73E−02 1.09 0.774 2033 C02 229956337 rs9288639 C 0.076 10621 1.18E−03 1.26 0.093 1697 1.45E−02 1.18 0.088 2030 C01 148893831 rs2495392 G 0.274 10629 1.18E−03 1.15 0.303 1700 7.91E−03 1.11 0.296 2034 C12 9208040 rs3213831 T 0.547 10635 1.18E−03 1.14 0.579 1700 8.97E−03 1.1 0.571 2034 C14 63868848 rs1953416 T 0.482 10627 1.18E−03 1.14 0.514 1698 4.79E−03 1.11 0.508 2032 C17 37372424 rs7210156 G 0.93 10631 1.18E−03 1.31 0.946 1699 3.16E−03 1.25 0.943 2033 C16 63942198 rs7192142 T 0.811 10602 1.18E−03 1.18 0.835 1693 2.07E−03 1.16 0.833 2025 C10 15465576 rs1013406 C 0.561 10623 1.18E−03 1.14 0.593 1697 1.35E−02 1.1 0.583 2030 C12 65812323 rs11835794 T 0.852 10635 1.18E−03 1.21 0.874 1700 1.80E−04 1.22 0.876 2034 C05 57500192 rs2112905 A 0.402 10635 1.19E−03 1.14 0.433 1700 4.16E−03 1.11 0.427 2034 C04 33363983 rs10517277 C 0.102 10629 1.19E−03 1.22 0.122 1700 3.92E−03 1.18 0.118 2034 C07 37924826 rs1357648 T 0.318 10602 1.20E−03 1.14 0.348 1691 2.54E−03 1.12 0.344 2024 C05 158795428 rs10045431 A 0.262 10582 1.20E−03 1.15 0.291 1675 6.80E−03 1.12 0.285 2007 C22 32522356 rs8135273 C 0.156 10593 1.20E−03 1.19 0.18 1689 9.52E−03 1.14 0.174 2020 C04 162467610 rs12503470 T 0.378 10632 1.20E−03 1.14 0.409 1700 4.24E−03 1.11 0.403 2034 C04 162156054 rs17359034 T 0.386 10551 1.20E−03 1.14 0.417 1700 1.11E−02 1.1 0.409 2034 C14 51013885 rs1458114 T 0.708 10457 1.21E−03 1.16 0.737 1653 4.43E−03 1.12 0.732 1982 C02 127990589 rs3943703 C 0.211 10632 1.21E−03 1.16 0.237 1700 5.13E−04 1.16 0.237 2034 C07 85202542 rs10276025 T 0.372 10635 1.22E−03 1.14 0.403 1700 1.23E−03 1.13 0.401 2034 C18 58474237 rs7241455 T 0.061 10635 1.22E−03 1.28 0.077 1700 3.10E−04 1.29 0.078 2034 C15 90437337 rs3743369 T 0.61 10633 1.22E−03 1.14 0.641 1700 8.00E−04 1.13 0.639 2034 C03 72701976 rs2046867 T 0.276 10630 1.23E−03 1.15 0.305 1700 7.59E−03 1.11 0.298 2034 C05 52576529 rs38055 T 0.383 10632 1.23E−03 1.14 0.414 1700 3.56E−05 1.17 0.42 2034 C08 70844508 rs7015359 G 0.186 10635 1.23E−03 1.17 0.211 1700 1.45E−03 1.16 0.209 2034 C17 17015262 rs4401079 T 0.21 10418 1.23E−03 1.17 0.236 1666 3.95E−04 1.17 0.237 1992 C10 23293068 rs10828393 C 0.891 10615 1.23E−03 1.24 0.91 1698 3.82E−03 1.19 0.907 2032 C14 57437666 rs11158238 T 0.141 10634 1.24E−03 1.19 0.163 1700 3.43E−03 1.16 0.16 2034 C08 97736809 rs1075479 A 0.79 10601 1.24E−03 1.17 0.815 1696 7.77E−03 1.13 0.81 2029 C07 21550808 rs4722054 G 0.087 10596 1.25E−03 1.24 0.105 1682 1.77E−03 1.21 0.103 2014 C22 34890870 rs763086 A 0.299 10624 1.26E−03 1.15 0.329 1699 2.88E−03 1.12 0.324 2031 C19 4187996 rs4740 A 0.269 10634 1.26E−03 1.15 0.298 1700 5.17E−03 1.12 0.292 2034 C12 75974496 rs7135414 A 0.914 10635 1.26E−03 1.27 0.931 1700 5.96E−03 1.21 0.928 2034 C12 75974496 rs7135414 A 0.914 10635 1.26E−03 1.27 0.931 1700 5.96E−03 1.21 0.928 2034 C05 5893171 rs864267 A 0.452 10633 1.26E−03 1.14 0.483 1700 1.57E−03 1.12 0.48 2034 C12 121504211 rs10847227 T 0.273 10616 1.26E−03 1.15 0.301 1700 1.46E−04 1.16 0.304 2034 C08 97440350 rs1992087 G 0.254 10635 1.27E−03 1.15 0.282 1700 2.92E−03 1.13 0.278 2034 C13 53306486 rs1993776 C 0.869 10635 1.28E−03 1.22 0.889 1700 2.60E−03 1.18 0.887 2034 C19 17080105 rs7246865 A 0.205 10635 1.28E−03 1.17 0.231 1700 3.11E−03 1.14 0.227 2034 C19 17080105 rs7246865 A 0.205 10635 1.28E−03 1.17 0.231 1700 3.11E−03 1.14 0.227 2034 C04 178163770 rs309800 C 0.798 10632 1.28E−03 1.18 0.823 1699 1.30E−04 1.2 0.826 2033 C05 57486156 rs2962014 G 0.501 10528 1.28E−03 1.14 0.533 1682 4.01E−03 1.11 0.528 2015 C19 14236895 rs7248277 C 0.563 10624 1.29E−03 1.14 0.594 1699 5.08E−04 1.14 0.594 2033 C01 30315299 rs407838 C 0.843 10633 1.29E−03 1.2 0.865 1700 7.85E−04 1.19 0.865 2034 C01 184669059 rs2250227 C 0.337 10635 1.29E−03 1.14 0.367 1700 3.60E−03 1.12 0.362 2034 C04 17186841 rs2697684 G 0.771 10635 1.29E−03 1.17 0.798 1700 1.46E−03 1.15 0.795 2034 C10 85007873 rs11199316 C 0.713 10568 1.29E−03 1.15 0.742 1687 1.02E−04 1.17 0.745 2019 CX 84984650 rs2213468 G 0.659 8219 1.30E−03 1.18 0.696 1094 2.51E−03 1.16 0.691 1307 CX 66115625 rs2031751 C 0.941 8270 1.30E−03 1.44 0.959 1102 8.21E−03 1.31 0.955 1315 C02 212342079 rs4442936 G 0.282 10600 1.32E−03 1.15 0.311 1683 9.92E−04 1.14 0.309 2016 C01 162568432 rs2651860 T 0.786 10635 1.32E−03 1.17 0.811 1700 4.88E−03 1.14 0.806 2033 C02 135143228 rs10496721 T 0.17 10631 1.32E−03 1.18 0.195 1699 6.12E−03 1.14 0.189 2033 C04 129841129 rs6534683 T 0.646 10635 1.32E−03 1.14 0.676 1700 8.61E−04 1.14 0.675 2034 C05 108055795 rs4957775 G 0.832 10635 1.33E−03 1.19 0.855 1700 1.22E−03 1.18 0.853 2034 C13 21281716 rs1887263 A 0.204 10630 1.33E−03 1.16 0.229 1700 1.56E−03 1.15 0.227 2034 C12 120804218 rs1169081 C 0.692 10626 1.33E−03 1.15 0.721 1700 2.42E−02 1.09 0.711 2034 C11 68636018 rs7111999 G 0.47 10494 1.33E−03 1.14 0.502 1666 1.94E−02 1.09 0.492 1994 C13 36900184 rs9566343 T 0.814 10634 1.34E−03 1.18 0.838 1700 9.66E−04 1.17 0.837 2034 C12 22807863 rs16925384 A 0.194 10621 1.34E−03 1.17 0.219 1699 1.79E−03 1.15 0.216 2033 C01 149009396 rs949969 T 0.195 10635 1.34E−03 1.17 0.221 1700 2.26E−03 1.15 0.218 2034 C14 64466293 rs894921 G 0.377 10633 1.35E−03 1.14 0.408 1700 1.12E−02 1.1 0.4 2034 C10 15419285 rs11596590 T 0.559 10634 1.35E−03 1.14 0.59 1699 1.36E−02 1.1 0.581 2033 C11 90747051 rs1436622 A 0.686 10633 1.35E−03 1.15 0.715 1700 5.93E−04 1.15 0.715 2034 C08 129199390 rs10505507 A 0.924 10634 1.36E−03 1.29 0.94 1700 5.90E−03 1.22 0.937 2034 C18 45713028 rs1790778 G 0.512 10632 1.36E−03 1.13 0.544 1699 1.91E−03 1.12 0.54 2033 C07 85200311 rs2373018 G 0.372 10635 1.36E−03 1.14 0.403 1700 1.35E−03 1.13 0.401 2034 C14 57397846 rs10483707 A 0.139 10635 1.36E−03 1.19 0.161 1700 5.05E−03 1.15 0.157 2034 C20 5929566 rs236113 T 0.883 10635 1.37E−03 1.23 0.902 1700 3.33E−03 1.19 0.899 2034 C07 11501113 rs1526543 T 0.829 10634 1.37E−03 1.19 0.852 1700 3.94E−03 1.15 0.849 2034 C05 5904611 rs2617549 A 0.453 10629 1.38E−03 1.13 0.485 1700 1.57E−03 1.12 0.482 2034 C02 36022756 rs6747236 T 0.716 10628 1.38E−03 1.15 0.744 1700 4.89E−04 1.15 0.744 2034 C10 8304796 rs7092384 C 0.86 10629 1.39E−03 1.21 0.881 1700 1.31E−03 1.19 0.88 2034 C02 42505686 rs6724757 A 0.09 10631 1.40E−03 1.23 0.109 1699 3.19E−04 1.24 0.109 2033 C05 66155122 rs2441109 G 0.162 10633 1.40E−03 1.18 0.186 1700 1.58E−02 1.12 0.179 2034 C10 131748550 rs1484652 T 0.905 10635 1.40E−03 1.26 0.923 1700 8.26E−03 1.19 0.919 2034 C16 2010569 rs2286472 C 0.269 10627 1.40E−03 1.15 0.297 1690 2.09E−03 1.13 0.294 2024 C05 39122462 rs6880882 A 0.352 10599 1.41E−03 1.14 0.382 1697 3.56E−03 1.12 0.377 2028 C16 88204775 rs4075964 A 0.284 10632 1.41E−03 1.15 0.312 1699 1.71E−03 1.13 0.31 2033 C09 28113402 rs1452335 G 0.715 10614 1.41E−03 1.15 0.744 1694 6.47E−04 1.15 0.743 2027 C14 31305463 rs1950216 T 0.798 10634 1.41E−03 1.18 0.823 1700 3.06E−03 1.15 0.82 2034 C13 45766462 rs9526329 G 0.921 10632 1.41E−03 1.28 0.938 1700 3.25E−03 1.23 0.935 2034 C11 14150002 rs10832223 T 0.837 10626 1.41E−03 1.19 0.86 1700 2.90E−03 1.16 0.857 2034 C02 77672532 rs2861078 T 0.57 10635 1.42E−03 1.14 0.601 1700 1.64E−03 1.12 0.599 2034 C01 62762582 rs11208061 A 0.345 10547 1.42E−03 1.14 0.375 1697 3.56E−03 1.12 0.37 2029 C20 49529811 rs4811008 G 0.461 10463 1.42E−03 1.14 0.493 1668 3.89E−03 1.11 0.488 1996 C14 102711567 rs8016595 C 0.754 10630 1.43E−03 1.16 0.781 1700 4.46E−03 1.13 0.776 2034 C01 243972662 rs12068067 G 0.776 10589 1.43E−03 1.17 0.801 1695 9.78E−04 1.16 0.8 2029 C10 84836912 rs10787854 A 0.83 10634 1.43E−03 1.19 0.853 1700 2.82E−04 1.2 0.854 2034 CX 55725022 rs5914778 G 0.802 8269 1.44E−03 1.22 0.832 1103 6.95E−04 1.22 0.831 1316 C05 102584028 rs183752 T 0.716 10621 1.44E−03 1.15 0.744 1699 1.26E−02 1.11 0.736 2033 C14 31304803 rs991387 G 0.799 10634 1.44E−03 1.18 0.823 1700 3.12E−03 1.15 0.82 2034 C11 68632276 rs1005858 G 0.47 10634 1.45E−03 1.13 0.502 1700 2.30E−02 1.09 0.491 2034 C03 195828700 rs4497978 A 0.667 10576 1.45E−03 1.15 0.696 1682 2.58E−03 1.13 0.693 2012 C05 40656007 rs13175020 T 0.816 10632 1.46E−03 1.18 0.84 1699 4.64E−04 1.19 0.841 2033 C01 62822706 rs6696619 C 0.662 10624 1.46E−03 1.14 0.692 1700 6.63E−04 1.14 0.691 2034 C13 104637486 rs354438 T 0.351 10634 1.46E−03 1.14 0.381 1700 5.60E−04 1.14 0.381 2034 C14 64464393 rs1147437 G 0.38 10634 1.46E−03 1.14 0.411 1700 8.57E−03 1.1 0.403 2034 C17 295873 rs4130140 A 0.175 10635 1.46E−03 1.17 0.199 1700 4.28E−03 1.14 0.195 2034 C07 20937657 rs2110007 C 0.943 10606 1.47E−03 1.34 0.956 1699 1.90E−03 1.3 0.955 2030 C21 26986173 rs2251540 G 0.642 10633 1.47E−03 1.14 0.672 1700 7.17E−04 1.14 0.671 2034 C10 23311212 rs993352 G 0.883 10593 1.47E−03 1.23 0.903 1689 4.02E−03 1.19 0.9 2021 C04 139831081 rs7669668 T 0.119 10635 1.48E−03 1.2 0.139 1700 1.69E−02 1.14 0.133 2034 C02 172634850 rs1399959 G 0.669 10611 1.48E−03 1.14 0.698 1699 1.32E−02 1.1 0.69 2032 C06 127842427 rs11154416 G 0.76 10566 1.49E−03 1.16 0.787 1684 5.06E−03 1.13 0.782 2016 C12 22797592 rs2171392 A 0.194 10635 1.49E−03 1.17 0.219 1700 2.03E−03 1.15 0.217 2034 C07 17747986 rs11766489 T 0.423 10635 1.49E−03 1.13 0.454 1700 1.74E−03 1.12 0.451 2034 C20 4116799 rs6084644 G 0.436 10635 1.49E−03 1.13 0.467 1700 2.33E−03 1.12 0.464 2034 C20 4116799 rs6084644 G 0.436 10635 1.49E−03 1.13 0.467 1700 2.33E−03 1.12 0.464 2034 C18 70239058 rs4892210 A 0.192 10634 1.49E−03 1.17 0.217 1700 8.76E−04 1.16 0.216 2034 C01 153057498 rs822519 A 0.932 10635 1.50E−03 1.3 0.947 1700 8.24E−04 1.3 0.946 2034 C10 5181871 rs4880711 C 0.35 10503 1.51E−03 1.14 0.38 1693 2.56E−02 1.09 0.37 2017 C14 101394200 rs10129841 A 0.577 10634 1.51E−03 1.14 0.608 1700 4.86E−03 1.11 0.603 2034 C07 38982261 rs4478468 G 0.31 10635 1.52E−03 1.14 0.339 1700 1.46E−03 1.13 0.337 2034 C08 39425796 rs7830101 T 0.274 10556 1.53E−03 1.15 0.302 1686 2.51E−03 1.13 0.299 2019 C16 19860174 rs1634675 G 0.787 10633 1.53E−03 1.17 0.812 1700 6.40E−03 1.13 0.807 2034 C08 75342454 rs6996971 C 0.476 10603 1.53E−03 1.13 0.507 1698 2.99E−04 1.14 0.509 2032 C05 102596616 rs26821 A 0.709 10628 1.53E−03 1.15 0.737 1697 1.27E−02 1.11 0.73 2031 C19 330003 rs10414677 T 0.276 10341 1.53E−03 1.15 0.305 1639 1.23E−02 1.11 0.297 1956 C14 64458802 rs1147443 T 0.254 10635 1.54E−03 1.15 0.281 1700 2.45E−03 1.13 0.278 2034 C11 108465132 rs1509729 G 0.688 10634 1.55E−03 1.15 0.717 1700 9.48E−03 1.11 0.71 2034 C05 176640493 rs7724098 G 0.289 10627 1.55E−03 1.14 0.317 1697 2.16E−03 1.13 0.314 2031 C03 54346463 rs1530733 A 0.156 10635 1.55E−03 1.18 0.179 1700 3.48E−03 1.15 0.176 2034 C16 88263882 rs904800 G 0.38 10635 1.55E−03 1.14 0.411 1700 5.04E−03 1.11 0.405 2034 C22 34142107 rs2071744 C 0.78 10607 1.55E−03 1.17 0.806 1700 5.19E−03 1.13 0.801 2033 C07 136071365 rs324594 C 0.27 10632 1.55E−03 1.15 0.298 1700 7.92E−04 1.14 0.297 2034 C07 102722901 rs10282605 C 0.187 10633 1.55E−03 1.17 0.211 1700 9.25E−03 1.13 0.206 2034 C04 37546025 rs3849018 T 0.279 10635 1.55E−03 1.15 0.307 1700 2.28E−03 1.13 0.304 2033 C05 97972689 rs168654 T 0.636 10630 1.56E−03 1.14 0.665 1699 5.48E−03 1.11 0.66 2033 C06 28156603 rs203877 T 0.729 10461 1.56E−03 1.16 0.757 1666 1.78E−02 1.1 0.748 1992 C05 76862558 rs251470 T 0.439 10634 1.56E−03 1.13 0.47 1700 6.26E−03 1.11 0.464 2034 C09 122155539 rs3780680 T 0.452 10610 1.56E−03 1.13 0.483 1698 2.92E−02 1.08 0.472 2031 C04 10657250 rs10011464 T 0.462 10581 1.56E−03 1.13 0.493 1685 2.56E−03 1.12 0.49 2016 C08 143147459 rs11167132 T 0.218 10568 1.57E−03 1.16 0.244 1693 3.04E−03 1.14 0.241 2027 CX 66121372 rs1576059 T 0.941 8273 1.57E−03 1.43 0.958 1103 9.27E−03 1.31 0.954 1316 C16 82550760 rs10514560 C 0.732 10632 1.57E−03 1.15 0.759 1700 2.17E−03 1.14 0.756 2034 C20 57601797 rs486921 C 0.853 10634 1.58E−03 1.2 0.875 1699 7.96E−04 1.2 0.875 2033 C17 14301595 rs2856177 A 0.622 10630 1.59E−03 1.14 0.652 1700 6.13E−03 1.11 0.647 2034 C01 63947687 rs2806535 A 0.487 10630 1.59E−03 1.13 0.519 1700 2.11E−03 1.12 0.515 2034 C22 18426996 rs3804044 T 0.858 10612 1.59E−03 1.2 0.879 1700 4.62E−03 1.17 0.876 2034 C19 50054507 rs377702 T 0.384 10629 1.61E−03 1.14 0.415 1700 1.75E−03 1.12 0.412 2034 C18 55144365 rs4806 C 0.284 10592 1.61E−03 1.15 0.312 1686 4.58E−03 1.12 0.307 2020 C08 75320456 rs4410896 A 0.479 10635 1.61E−03 1.13 0.51 1700 4.67E−04 1.14 0.511 2034 C13 43040379 rs963569 A 0.748 10635 1.61E−03 1.16 0.775 1700 4.72E−02 1.09 0.764 2034 CX 69317680 rs2341629 C 0.467 8261 1.62E−03 1.16 0.505 1103 1.66E−03 1.15 0.502 1316 C11 17901963 rs2237921 C 0.156 10634 1.62E−03 1.18 0.179 1700 6.00E−03 1.14 0.174 2034 C10 84972068 rs11199158 G 0.608 10635 1.62E−03 1.14 0.638 1700 2.26E−05 1.17 0.645 2034 C11 1390257 rs4963076 T 0.482 10635 1.62E−03 1.13 0.513 1700 3.68E−03 1.11 0.508 2034 C11 1390257 rs4963076 T 0.482 10635 1.62E−03 1.13 0.513 1700 3.68E−03 1.11 0.508 2034 C15 52585989 rs2553223 G 0.346 10626 1.62E−03 1.14 0.376 1700 6.64E−04 1.14 0.376 2034 C08 32791061 rs16880128 G 0.446 10541 1.63E−03 1.13 0.477 1693 9.35E−03 1.1 0.47 2026 C08 96746644 rs3134517 G 0.64 10632 1.63E−03 1.14 0.67 1700 7.83E−03 1.11 0.663 2033 C01 55121739 rs4927219 G 0.601 10635 1.63E−03 1.14 0.631 1700 3.78E−04 1.14 0.632 2034 C14 19276803 rs10872856 C 0.912 10635 1.63E−03 1.26 0.929 1700 1.56E−02 1.18 0.924 2034 C01 148792338 rs1970568 T 0.813 10634 1.64E−03 1.18 0.837 1700 2.08E−03 1.16 0.835 2034 C12 20945636 rs3764006 C 0.104 10626 1.64E−03 1.21 0.123 1700 8.33E−04 1.21 0.123 2034 C18 45732885 rs1557359 G 0.407 10635 1.64E−03 1.13 0.437 1700 1.64E−03 1.12 0.435 2034 C17 14260485 rs2323095 A 0.663 10635 1.64E−03 1.14 0.692 1700 3.76E−03 1.12 0.688 2034 C08 96745945 rs3102526 G 0.64 10635 1.65E−03 1.14 0.669 1700 7.97E−03 1.11 0.663 2034 C04 96606254 rs6850673 C 0.141 10631 1.65E−03 1.19 0.163 1700 2.15E−03 1.17 0.161 2034 C22 18449129 rs2073778 C 0.858 10635 1.65E−03 1.2 0.879 1700 5.41E−03 1.16 0.875 2034 C07 116742325 rs2027945 A 0.19 10631 1.66E−03 1.17 0.215 1700 1.06E−03 1.16 0.214 2034 C07 144298585 rs7791708 A 0.677 10614 1.66E−03 1.14 0.706 1693 4.26E−03 1.12 0.701 2027 C05 3977821 rs11956711 C 0.066 10608 1.66E−03 1.26 0.082 1698 4.36E−03 1.22 0.08 2031 C05 39071087 rs9292729 C 0.338 10625 1.66E−03 1.14 0.368 1700 6.86E−03 1.11 0.362 2034 C01 29291511 rs10799128 T 0.196 10601 1.66E−03 1.16 0.221 1686 3.50E−03 1.14 0.217 2020 C05 3595286 rs1697997 A 0.914 10635 1.66E−03 1.26 0.931 1700 5.14E−03 1.21 0.928 2034 C02 215347262 rs10932529 A 0.247 10635 1.67E−03 1.15 0.274 1700 1.88E−03 1.14 0.272 2034 CX 6130802 rs7892324 C 0.165 8255 1.67E−03 1.22 0.194 1093 3.38E−03 1.19 0.19 1306 C12 62930978 rs10878126 G 0.493 10634 1.67E−03 1.13 0.524 1700 6.47E−04 1.13 0.525 2034 C04 44935711 rs6447404 G 0.617 10633 1.67E−03 1.14 0.647 1700 1.07E−02 1.1 0.639 2034 C03 145977000 rs10935523 A 0.741 10632 1.68E−03 1.16 0.767 1700 7.37E−03 1.12 0.762 2034 C16 79586916 rs7188879 T 0.964 10629 1.69E−03 1.45 0.975 1699 7.87E−03 1.33 0.972 2033 C05 159076573 rs889053 T 0.162 10634 1.69E−03 1.18 0.185 1700 3.69E−03 1.15 0.182 2034 C11 91175735 rs808003 T 0.554 10634 1.69E−03 1.13 0.585 1700 2.62E−02 1.09 0.574 2034 C17 14258654 rs12449610 T 0.669 10635 1.69E−03 1.14 0.697 1700 3.74E−03 1.12 0.693 2034 C04 3811449 rs6822427 A 0.487 10635 1.70E−03 1.13 0.518 1700 2.14E−03 1.12 0.515 2034 C01 218934430 rs1519463 G 0.5 10635 1.70E−03 1.13 0.531 1700 4.65E−04 1.14 0.532 2034 C02 183549717 rs4666836 T 0.22 10633 1.70E−03 1.16 0.246 1699 3.72E−03 1.13 0.242 2033 C03 62438401 rs1452075 T 0.734 10549 1.70E−03 1.15 0.761 1692 5.65E−03 1.12 0.756 2019 C03 62438401 rs1452075 T 0.734 10549 1.70E−03 1.15 0.761 1692 5.65E−03 1.12 0.756 2019 C10 15387774 rs2138930 T 0.11 10620 1.71E−03 1.21 0.129 1700 8.36E−03 1.16 0.125 2033 C12 6177827 rs797773 T 0.394 10607 1.71E−03 1.13 0.425 1698 2.20E−03 1.12 0.422 2031 C12 52152886 rs784563 G 0.441 10631 1.71E−03 1.13 0.472 1700 1.70E−03 1.12 0.47 2034 C01 113143551 rs773588 C 0.276 10632 1.71E−03 1.15 0.304 1700 2.18E−04 1.16 0.307 2034 C05 66177928 rs39700 G 0.374 10631 1.72E−03 1.13 0.404 1699 1.04E−02 1.1 0.396 2033 C11 132266819 rs1395504 A 0.493 10634 1.72E−03 1.13 0.524 1700 3.66E−03 1.11 0.519 2034 C18 70236272 rs1365254 T 0.192 10634 1.73E−03 1.16 0.217 1700 1.01E−03 1.16 0.216 2034 C05 38927129 rs525735 C 0.774 10632 1.74E−03 1.16 0.799 1699 1.06E−02 1.12 0.793 2033 C08 75357793 rs10283076 G 0.477 10627 1.74E−03 1.13 0.507 1698 3.56E−04 1.14 0.509 2032 C10 108671040 rs1337430 A 0.788 10215 1.74E−03 1.17 0.813 1685 9.30E−03 1.13 0.807 2014 C18 55191365 rs9319948 A 0.283 10629 1.75E−03 1.14 0.311 1700 4.57E−03 1.12 0.306 2034 C15 30230982 rs4779984 G 0.1 10616 1.75E−03 1.22 0.119 1698 9.51E−04 1.21 0.119 2032 C10 33672138 rs2804453 G 0.111 10621 1.76E−03 1.21 0.131 1697 8.26E−03 1.16 0.126 2030 C21 40710416 rs1882757 A 0.506 10635 1.76E−03 1.13 0.536 1700 2.56E−03 1.12 0.533 2034 C06 39827103 rs9471170 G 0.885 10635 1.77E−03 1.22 0.904 1700 1.10E−02 1.16 0.899 2034 C09 28154645 rs2044961 G 0.571 10633 1.77E−03 1.13 0.601 1700 7.85E−04 1.13 0.601 2034 C10 94841520 rs10509657 C 0.099 10631 1.78E−03 1.22 0.118 1700 3.06E−03 1.19 0.115 2034 C12 101677726 rs2247919 T 0.738 10635 1.79E−03 1.15 0.764 1700 6.44E−03 1.12 0.759 2034 C02 11287711 rs7608117 T 0.486 10629 1.79E−03 1.13 0.517 1698 4.79E−03 1.11 0.512 2031 C01 31037636 rs12126748 A 0.345 10489 1.79E−03 1.14 0.375 1665 5.15E−03 1.11 0.37 1995 C03 63602103 rs7653410 C 0.319 10620 1.79E−03 1.14 0.348 1700 1.04E−02 1.1 0.341 2034 C17 70788248 rs2041088 A 0.719 10633 1.79E−03 1.15 0.747 1700 3.91E−03 1.13 0.743 2034 C06 36751662 rs1864750 G 0.248 10635 1.80E−03 1.15 0.275 1700 2.56E−04 1.16 0.277 2034 C11 12971706 rs3935878 T 0.738 10634 1.80E−03 1.15 0.764 1700 5.90E−03 1.12 0.76 2034 C12 67493429 rs1470383 C 0.143 10634 1.81E−03 1.18 0.165 1700 3.15E−03 1.16 0.162 2034 C05 56037706 rs7720499 T 0.112 10635 1.81E−03 1.2 0.132 1700 3.98E−03 1.17 0.129 2033 C02 172714469 rs951917 T 0.387 10634 1.83E−03 1.13 0.417 1700 1.00E−02 1.1 0.41 2034 C03 6764265 rs12491369 G 0.571 10634 1.83E−03 1.13 0.601 1700 9.89E−04 1.13 0.601 2034 C06 79771759 rs9352688 A 0.623 10384 1.83E−03 1.14 0.653 1662 2.17E−03 1.12 0.65 1991 C19 446722 rs758503 T 0.294 10524 1.83E−03 1.14 0.323 1686 3.19E−03 1.12 0.319 2018 C03 74187210 rs4234186 A 0.943 10617 1.83E−03 1.33 0.957 1697 8.06E−03 1.25 0.954 2031 C07 16590961 rs706076 G 0.146 10619 1.83E−03 1.18 0.169 1700 1.53E−02 1.13 0.162 2034 C02 76317619 rs7563058 C 0.504 10635 1.84E−03 1.13 0.535 1700 2.64E−03 1.12 0.531 2034 C04 175513600 rs4695894 G 0.5 10632 1.84E−03 1.13 0.53 1700 2.89E−03 1.11 0.527 2034 C17 18352177 rs2746025 G 0.641 10635 1.84E−03 1.14 0.671 1700 2.07E−03 1.13 0.668 2034 C07 28337194 rs10486588 G 0.231 10616 1.85E−03 1.15 0.258 1694 3.86E−03 1.13 0.254 2028 C06 39793734 rs9296304 A 0.498 10635 1.85E−03 1.13 0.529 1700 9.98E−03 1.1 0.521 2034 C13 20599475 rs4770252 A 0.802 10626 1.86E−03 1.17 0.826 1699 4.75E−04 1.18 0.827 2032 C04 178964553 rs1983130 G 0.414 10625 1.86E−03 1.13 0.444 1699 3.12E−03 1.12 0.441 2033 C02 39306628 rs2168043 C 0.868 10635 1.86E−03 1.21 0.888 1700 2.99E−03 1.18 0.886 2034 C06 105791384 rs1149305 T 0.059 10544 1.87E−03 1.28 0.074 1695 1.49E−03 1.26 0.074 2027 C22 18432012 rs5992507 A 0.858 10633 1.87E−03 1.2 0.879 1700 5.40E−03 1.16 0.876 2034 C13 53208642 rs2050972 C 0.878 10635 1.87E−03 1.22 0.897 1700 6.10E−03 1.17 0.894 2034 C03 66633156 rs1563545 G 0.523 10562 1.87E−03 1.13 0.553 1681 2.31E−03 1.12 0.55 2014 C03 7494813 rs752299 T 0.685 10633 1.87E−03 1.14 0.714 1700 3.80E−03 1.12 0.71 2034 C01 173267354 rs12033847 T 0.462 10416 1.88E−03 1.13 0.493 1668 2.13E−03 1.12 0.49 1988 C07 147146014 rs10271435 A 0.06 10631 1.88E−03 1.27 0.076 1700 2.74E−04 1.3 0.077 2034 C03 29295798 rs13079598 A 0.905 10635 1.88E−03 1.25 0.923 1700 5.92E−03 1.2 0.92 2034 CX 143133206 rs11094472 G 0.787 8262 1.89E−03 1.21 0.817 1098 3.45E−03 1.18 0.814 1311 C07 116708662 rs2237724 A 0.19 10635 1.90E−03 1.16 0.215 1700 1.21E−03 1.16 0.214 2034 C07 116694598 rs10487368 T 0.19 10635 1.90E−03 1.16 0.215 1700 1.21E−03 1.16 0.214 2034 C07 116702050 rs2237723 T 0.193 10630 1.90E−03 1.16 0.217 1700 1.05E−03 1.16 0.217 2034 C02 173071729 rs6718013 G 0.538 10634 1.91E−03 1.13 0.568 1700 1.45E−02 1.09 0.56 2034 C03 7486375 rs779710 A 0.589 10634 1.91E−03 1.13 0.619 1700 1.47E−03 1.13 0.617 2034 C07 38853360 rs1525798 G 0.303 10635 1.91E−03 1.14 0.331 1700 1.23E−03 1.13 0.33 2034 C18 53741253 rs4940582 G 0.849 10631 1.91E−03 1.19 0.871 1699 1.77E−03 1.18 0.869 2033 C04 161577318 rs17326199 G 0.211 10634 1.91E−03 1.16 0.237 1699 8.27E−03 1.12 0.231 2033 C13 20622774 rs9285207 C 0.195 10608 1.91E−03 1.16 0.22 1693 1.89E−03 1.15 0.218 2026 C08 75316641 rs10504576 A 0.478 10551 1.92E−03 1.13 0.509 1677 5.94E−04 1.13 0.51 2010 C14 92766673 rs2281519 T 0.257 10633 1.92E−03 1.15 0.284 1700 5.98E−03 1.12 0.279 2033 C15 37096582 rs1841441 A 0.466 10634 1.92E−03 1.13 0.496 1700 1.15E−03 1.13 0.496 2034 C10 84843813 rs2349157 G 0.855 10635 1.93E−03 1.2 0.876 1700 9.76E−04 1.19 0.876 2034 C05 167524725 rs2617972 C 0.808 10632 1.93E−03 1.17 0.832 1699 9.94E−03 1.13 0.827 2033 C12 96022770 rs989264 A 0.041 10635 1.93E−03 1.33 0.054 1700 1.86E−03 1.31 0.053 2034 C06 10958298 rs9357002 T 0.631 10453 1.93E−03 1.14 0.66 1678 4.72E−03 1.11 0.655 2007 C04 147453178 rs723794 T 0.764 10635 1.94E−03 1.16 0.79 1700 5.53E−03 1.13 0.785 2034 C11 127732102 rs7933433 G 0.648 10633 1.95E−03 1.14 0.677 1699 1.69E−03 1.13 0.675 2033 C03 5243162 rs341973 A 0.51 10634 1.95E−03 1.13 0.541 1700 1.92E−02 1.09 0.531 2034 C22 18482283 rs2238798 G 0.858 10633 1.95E−03 1.2 0.879 1700 6.39E−03 1.16 0.875 2034 C10 65928341 rs990828 G 0.416 10631 1.96E−03 1.13 0.446 1700 1.23E−02 1.1 0.438 2034 C08 143121983 rs7834060 G 0.434 10635 1.96E−03 1.13 0.464 1700 2.51E−03 1.12 0.461 2034 C01 184791657 rs1339083 A 0.34 10635 1.96E−03 1.14 0.369 1700 1.56E−03 1.13 0.367 2034 C11 92444704 rs9971402 C 0.872 10633 1.96E−03 1.21 0.892 1700 5.09E−04 1.22 0.893 2034 C04 162770424 rs958247 A 0.287 10626 1.96E−03 1.14 0.315 1700 1.64E−03 1.13 0.314 2034 C07 150069821 rs2373885 A 0.75 10631 1.96E−03 1.16 0.776 1700 8.98E−04 1.15 0.776 2034 C08 139195557 rs4909759 T 0.261 10633 1.96E−03 1.15 0.288 1700 7.46E−03 1.12 0.282 2034 C02 209737500 rs9288396 T 0.204 10635 1.97E−03 1.16 0.229 1700 1.09E−03 1.15 0.229 2034 C01 40520068 rs7524868 G 0.306 10611 1.97E−03 1.14 0.334 1691 3.27E−02 1.09 0.324 2024 C06 79657373 rs10943606 G 0.746 10632 1.97E−03 1.15 0.772 1700 1.90E−03 1.14 0.771 2033 C16 2014037 rs3785284 C 0.265 10571 1.98E−03 1.15 0.292 1698 2.17E−03 1.13 0.29 2032 C02 215385419 rs2216544 A 0.253 10635 1.98E−03 1.15 0.28 1700 2.46E−03 1.13 0.278 2034 C17 53871788 rs9895713 G 0.176 10633 1.98E−03 1.17 0.2 1700 2.03E−03 1.15 0.198 2034 C03 2631107 rs17565216 C 0.363 10631 1.98E−03 1.13 0.392 1699 9.20E−04 1.13 0.392 2033 C07 116815796 rs213987 T 0.327 10632 1.99E−03 1.14 0.356 1700 3.83E−03 1.12 0.352 2034 C07 116815796 rs213987 T 0.327 10632 1.99E−03 1.14 0.356 1700 3.83E−03 1.12 0.352 2034 C03 175238582 rs1549100 T 0.73 10574 1.99E−03 1.15 0.757 1693 3.92E−02 1.09 0.747 2026 C06 69212746 rs9454539 A 0.877 10630 1.99E−03 1.21 0.896 1699 9.23E−04 1.21 0.896 2033 C01 65243954 rs3818513 C 0.457 10635 1.99E−03 1.13 0.488 1700 5.23E−02 1.07 0.475 2034 C12 123074369 rs4765477 T 0.044 10632 1.99E−03 1.32 0.057 1700 3.78E−03 1.27 0.056 2034 C02 118543519 rs1477451 T 0.124 10635 2.00E−03 1.19 0.145 1700 2.98E−02 1.12 0.137 2034 C08 143128135 rs3934930 T 0.433 10635 2.00E−03 1.13 0.464 1700 2.52E−03 1.12 0.461 2034 C07 81287212 rs6467882 C 0.165 10631 2.00E−03 1.17 0.188 1700 1.69E−03 1.16 0.187 2034 C01 155206460 rs4971177 T 0.913 10634 2.00E−03 1.26 0.93 1700 8.85E−04 1.26 0.93 2034 C06 119414590 rs1360782 A 0.348 10634 2.01E−03 1.13 0.378 1700 1.44E−03 1.13 0.376 2034 C07 50023386 rs12669163 C 0.297 10525 2.01E−03 1.14 0.325 1675 5.51E−03 1.12 0.321 2004 C07 16810246 rs1029577 T 0.319 10625 2.02E−03 1.14 0.347 1697 2.55E−03 1.12 0.345 2031 C04 82277070 rs10026120 T 0.96 10616 2.03E−03 1.4 0.971 1699 7.73E−03 1.31 0.969 2029 C05 133913277 rs1476097 T 0.656 10629 2.03E−03 1.14 0.685 1699 4.64E−04 1.15 0.686 2032 C07 13679025 rs3735344 G 0.421 10583 2.04E−03 1.13 0.451 1687 7.75E−03 1.1 0.445 2021 C17 7878493 rs4791759 A 0.038 10621 2.05E−03 1.34 0.051 1699 5.53E−03 1.28 0.048 2031 C05 14319911 rs30616 T 0.852 10634 2.05E−03 1.19 0.873 1700 4.29E−03 1.16 0.87 2034 C06 143011798 rs478884 A 0.879 10635 2.05E−03 1.22 0.898 1700 7.23E−04 1.22 0.898 2034 C14 47996364 rs12436454 T 0.713 10592 2.05E−03 1.15 0.74 1697 4.47E−03 1.12 0.736 2030 C09 23762277 rs7038525 T 0.152 10629 2.05E−03 1.18 0.174 1700 4.27E−04 1.19 0.176 2034 C06 69230698 rs10806602 T 0.877 10614 2.06E−03 1.21 0.897 1696 1.03E−03 1.21 0.897 2030 C11 17918391 rs3993323 A 0.14 10630 2.06E−03 1.18 0.162 1697 5.18E−03 1.15 0.159 2031 C18 35157614 rs12964741 A 0.667 10489 2.06E−03 1.14 0.695 1671 3.40E−04 1.15 0.698 2002 C08 73289641 rs10504537 A 0.879 10635 2.08E−03 1.22 0.899 1700 4.08E−04 1.23 0.9 2034 C06 72275474 rs12207816 A 0.914 10635 2.08E−03 1.26 0.93 1700 7.95E−04 1.26 0.93 2034 C19 4202069 rs1045750 C 0.265 10634 2.08E−03 1.14 0.292 1699 6.95E−03 1.12 0.287 2033 C02 203864322 rs6704822 G 0.912 10558 2.08E−03 1.26 0.929 1689 3.09E−03 1.22 0.927 2019 C01 173423432 rs2175177 A 0.465 10625 2.09E−03 1.13 0.495 1698 1.84E−03 1.12 0.493 2031 CX 115198464 rs2526763 G 0.365 8266 2.09E−03 1.17 0.401 1102 7.05E−03 1.13 0.394 1315 C11 134180799 rs1289455 T 0.147 10628 2.09E−03 1.18 0.169 1698 2.49E−03 1.16 0.167 2032 C01 238623817 rs3014559 A 0.546 10632 2.10E−03 1.13 0.576 1700 2.98E−03 1.12 0.573 2034 C02 76254681 rs317285 A 0.504 10634 2.10E−03 1.13 0.534 1700 2.98E−03 1.11 0.531 2034 C08 37465414 rs7017907 C 0.083 10598 2.10E−03 1.23 0.101 1691 6.65E−03 1.19 0.098 2024 C16 53597062 rs3751812 T 0.404 10627 2.10E−03 1.13 0.433 1699 3.87E−04 1.14 0.436 2033 C05 167526920 rs1077046 C 0.553 10633 2.10E−03 1.13 0.583 1700 1.46E−02 1.09 0.575 2034 C10 131748188 rs11597160 A 0.906 10635 2.11E−03 1.25 0.923 1700 1.05E−02 1.18 0.919 2034 C18 13442635 rs12964045 C 0.13 10634 2.11E−03 1.19 0.151 1700 8.59E−03 1.15 0.147 2034 C05 9694366 rs3213627 T 0.167 10630 2.13E−03 1.17 0.19 1700 4.17E−03 1.15 0.187 2034 C21 24693776 rs2829040 A 0.449 10633 2.13E−03 1.13 0.479 1700 1.51E−03 1.12 0.478 2034 C07 85269850 rs1012995 C 0.219 10600 2.13E−03 1.15 0.244 1685 1.45E−03 1.15 0.243 2019 C07 18443601 rs2269752 C 0.93 10630 2.13E−03 1.29 0.944 1700 8.19E−03 1.22 0.941 2034 C01 85995056 rs1360903 G 0.511 10626 2.14E−03 1.13 0.541 1700 5.66E−03 1.11 0.536 2033 C16 62628004 rs2962080 G 0.609 10631 2.15E−03 1.13 0.638 1699 2.28E−03 1.12 0.636 2033 C12 20081535 rs2417821 T 0.749 10635 2.15E−03 1.15 0.775 1700 1.80E−04 1.18 0.778 2034 C04 10634963 rs2170752 T 0.576 10634 2.16E−03 1.13 0.606 1700 2.79E−02 1.09 0.596 2034 C09 110310944 rs4979085 T 0.297 10629 2.16E−03 1.14 0.324 1700 2.97E−03 1.12 0.322 2034 C01 216145811 rs11118175 G 0.076 10635 2.16E−03 1.24 0.092 1700 2.03E−03 1.22 0.091 2034 C06 57080845 rs7756421 A 0.84 10188 2.16E−03 1.19 0.862 1690 4.45E−03 1.16 0.859 2019 C06 29594220 rs3094564 G 0.386 10635 2.17E−03 1.13 0.415 1700 4.26E−03 1.11 0.411 2034 C18 53282820 rs580647 A 0.886 10622 2.17E−03 1.22 0.904 1698 6.59E−03 1.18 0.901 2031 C14 63874253 rs7145500 A 0.661 10634 2.17E−03 1.14 0.69 1700 1.37E−03 1.13 0.689 2034 C02 218495194 rs1478581 G 0.819 10632 2.18E−03 1.18 0.841 1700 3.13E−03 1.15 0.839 2032 C13 102932541 rs1347329 C 0.592 10616 2.18E−03 1.13 0.621 1700 1.53E−02 1.09 0.614 2033 C05 39159439 rs444556 C 0.301 10632 2.18E−03 1.14 0.329 1700 3.08E−03 1.12 0.326 2034 C09 14600866 rs1343705 G 0.471 10631 2.18E−03 1.13 0.501 1699 3.38E−03 1.11 0.498 2033 C16 19038467 rs8053779 G 0.734 10634 2.19E−03 1.15 0.76 1700 1.04E−02 1.11 0.754 2034 C21 26972748 rs2830357 G 0.568 10634 2.19E−03 1.13 0.598 1700 1.78E−03 1.12 0.597 2034 C07 77798006 rs2192658 T 0.076 10630 2.19E−03 1.24 0.092 1699 1.17E−02 1.18 0.088 2032 C17 62590633 rs1985961 C 0.412 10633 2.20E−03 1.13 0.442 1700 2.23E−03 1.12 0.44 2034 C10 96398926 rs10509680 T 0.05 10601 2.20E−03 1.29 0.064 1695 9.38E−03 1.23 0.061 2027 C11 98634196 rs1461684 T 0.849 10635 2.20E−03 1.19 0.87 1700 8.48E−03 1.15 0.866 2034 C06 106231995 rs4440505 C 0.781 10635 2.20E−03 1.16 0.806 1700 5.16E−03 1.13 0.802 2034 C03 14269176 rs2128163 G 0.533 10617 2.21E−03 1.13 0.563 1700 2.43E−03 1.12 0.56 2034 C07 8516487 rs12234501 T 0.133 10635 2.22E−03 1.19 0.154 1700 6.54E−04 1.19 0.155 2034 C10 84892441 rs10886432 G 0.638 10634 2.22E−03 1.14 0.666 1700 1.76E−04 1.16 0.67 2034 C08 41405289 rs7819949 T 0.271 10634 2.23E−03 1.14 0.299 1700 4.46E−02 1.08 0.288 2034 C21 42743171 rs3788014 C 0.925 10631 2.23E−03 1.28 0.94 1700 2.98E−03 1.24 0.939 2033 C16 75032079 rs4243110 T 0.458 10628 2.23E−03 1.13 0.489 1699 4.24E−03 1.11 0.485 2033 C15 52604593 rs2414325 T 0.489 10634 2.23E−03 1.13 0.519 1700 1.35E−03 1.12 0.518 2034 C07 86657613 rs31662 G 0.862 10635 2.24E−03 1.2 0.882 1700 4.06E−03 1.17 0.88 2034 C01 148824678 rs6702842 G 0.269 10611 2.25E−03 1.14 0.296 1694 1.24E−02 1.11 0.289 2028 C06 28141066 rs149951 T 0.726 10635 2.25E−03 1.15 0.753 1700 2.41E−02 1.1 0.744 2034 C06 28335583 rs1635 G 0.942 10565 2.25E−03 1.32 0.955 1689 8.32E−03 1.24 0.953 2019 C16 53594877 rs8050136 A 0.404 10634 2.26E−03 1.13 0.433 1699 4.22E−04 1.14 0.436 2033 C19 48943265 rs346535 T 0.234 10635 2.26E−03 1.15 0.26 1700 4.17E−03 1.13 0.257 2034 C13 101270990 rs2038709 C 0.081 10629 2.26E−03 1.23 0.098 1700 1.17E−02 1.18 0.094 2034 C01 19425721 rs3748744 G 0.899 10634 2.26E−03 1.23 0.916 1700 2.68E−02 1.15 0.911 2034 C04 107037574 rs1982346 C 0.062 10480 2.27E−03 1.27 0.077 1682 1.13E−03 1.26 0.077 2011 C15 34830800 rs1194620 T 0.232 10633 2.27E−03 1.15 0.257 1700 9.03E−03 1.12 0.252 2034 C10 5948421 rs7912210 C 0.963 10616 2.28E−03 1.42 0.973 1679 5.95E−04 1.45 0.974 2012 C21 14334270 rs2822391 A 0.548 10634 2.28E−03 1.13 0.578 1700 8.05E−04 1.13 0.578 2034 C05 15952862 rs7715223 C 0.819 10597 2.28E−03 1.18 0.842 1692 1.73E−02 1.12 0.835 2026 C02 75385815 rs4853116 A 0.624 10364 2.29E−03 1.13 0.653 1695 2.15E−03 1.12 0.651 2025 C05 56050092 rs4700485 A 0.322 10635 2.29E−03 1.14 0.351 1700 1.00E−02 1.1 0.344 2034 C01 184820295 rs2383658 G 0.388 10633 2.29E−03 1.13 0.417 1700 1.58E−03 1.12 0.416 2034 C03 82844262 rs13075335 T 0.9 10058 2.29E−03 1.24 0.918 1678 9.58E−03 1.18 0.914 2004 C04 82322766 rs6830629 A 0.975 10625 2.30E−03 1.56 0.984 1699 8.03E−03 1.41 0.983 2032 C14 63868436 rs2411822 C 0.485 10630 2.30E−03 1.13 0.515 1700 9.77E−03 1.1 0.509 2034 C05 55844670 rs30365 C 0.898 10635 2.30E−03 1.23 0.915 1700 5.89E−03 1.19 0.912 2034 C06 29516393 rs2074464 T 0.445 10625 2.31E−03 1.13 0.475 1699 9.91E−03 1.1 0.469 2033 C06 29588861 rs3094572 A 0.386 10635 2.31E−03 1.13 0.416 1700 4.61E−03 1.11 0.412 2034 C01 218026319 rs2642438 G 0.71 10581 2.31E−03 1.14 0.737 1693 1.21E−02 1.11 0.731 2025 C14 101389489 rs4708 A 0.546 10627 2.31E−03 1.13 0.576 1698 4.92E−03 1.11 0.572 2030 C02 76278450 rs404892 C 0.505 10634 2.31E−03 1.13 0.535 1700 3.19E−03 1.11 0.532 2034 C11 1341537 rs7122936 A 0.572 10556 2.31E−03 1.13 0.602 1700 4.84E−03 1.11 0.598 2034 C11 1341537 rs7122936 A 0.572 10556 2.31E−03 1.13 0.602 1700 4.84E−03 1.11 0.598 2034 C05 56080018 rs12657615 C 0.115 10635 2.32E−03 1.2 0.135 1700 5.17E−03 1.17 0.132 2034 C14 64537666 rs6573648 G 0.274 10634 2.33E−03 1.14 0.301 1700 2.25E−03 1.13 0.299 2034 C17 70794100 rs2159010 A 0.727 10583 2.33E−03 1.15 0.753 1700 4.40E−03 1.13 0.75 2032 C07 46518795 rs956010 A 0.88 10635 2.33E−03 1.21 0.899 1700 2.09E−03 1.2 0.898 2034 C15 92040939 rs10152962 G 0.154 10635 2.33E−03 1.17 0.176 1700 7.80E−04 1.18 0.177 2034 C20 49591938 rs913670 C 0.631 10595 2.33E−03 1.13 0.66 1700 3.99E−03 1.12 0.656 2033 C20 57938553 rs6128397 G 0.689 10633 2.34E−03 1.14 0.716 1700 7.46E−03 1.11 0.711 2034 C21 21803122 rs2017705 C 0.073 10598 2.34E−03 1.24 0.089 1696 1.14E−02 1.19 0.086 2029 C05 3996863 rs634344 G 0.067 10633 2.34E−03 1.25 0.082 1700 6.05E−03 1.21 0.079 2033 C06 27418512 rs9461366 G 0.614 10635 2.34E−03 1.13 0.643 1700 6.05E−03 1.11 0.638 2034 C22 19648862 rs178260 T 0.14 10632 2.34E−03 1.18 0.161 1700 6.21E−03 1.15 0.158 2034 C09 112545345 rs2236388 G 0.899 10634 2.35E−03 1.23 0.917 1700 7.73E−04 1.24 0.917 2034 C07 19730452 rs10486378 G 0.277 10449 2.35E−03 1.14 0.304 1673 1.11E−02 1.11 0.298 2002 C05 6325742 rs1457122 T 0.333 10633 2.35E−03 1.13 0.361 1700 2.33E−03 1.12 0.359 2034 C08 92473760 rs2607102 T 0.927 10586 2.35E−03 1.28 0.942 1690 5.93E−03 1.23 0.939 2020 C06 165937562 rs9348022 T 0.657 10631 2.37E−03 1.14 0.685 1699 5.08E−03 1.12 0.681 2033 C10 78039047 rs1865017 C 0.734 10633 2.37E−03 1.15 0.76 1700 5.34E−03 1.12 0.756 2034 C13 45593565 rs9534568 A 0.76 10269 2.37E−03 1.15 0.785 1695 2.46E−03 1.14 0.783 2024 C08 32774151 rs9656744 T 0.511 10632 2.38E−03 1.13 0.541 1699 3.71E−03 1.11 0.537 2030 C09 68331465 rs943535 A 0.917 10584 2.39E−03 1.26 0.933 1690 9.80E−04 1.26 0.933 2020 C10 87769103 rs10749535 T 0.472 10635 2.40E−03 1.13 0.502 1700 2.92E−03 1.11 0.499 2034 C11 98579265 rs7120353 T 0.899 10634 2.40E−03 1.23 0.916 1700 2.08E−03 1.22 0.915 2034 C05 31377276 rs6875512 A 0.742 10632 2.40E−03 1.15 0.768 1700 7.97E−03 1.12 0.763 2034 C02 198322740 rs6434921 A 0.392 10635 2.40E−03 1.13 0.421 1700 1.59E−02 1.09 0.414 2034 C06 5382731 rs2113691 C 0.488 10479 2.40E−03 1.13 0.518 1644 3.11E−03 1.12 0.515 1974 C10 50087691 rs3793786 C 0.24 10635 2.40E−03 1.15 0.266 1700 4.64E−03 1.13 0.262 2034 C08 23073423 rs11775256 T 0.27 10634 2.41E−03 1.14 0.297 1700 9.12E−03 1.11 0.292 2034 C12 116686949 rs2592289 A 0.156 10632 2.41E−03 1.17 0.179 1700 2.57E−03 1.16 0.177 2034 C07 157067324 rs11769878 C 0.742 10433 2.41E−03 1.15 0.768 1690 2.84E−03 1.14 0.766 2022 C11 56669965 rs717117 G 0.075 10632 2.41E−03 1.24 0.091 1700 7.09E−03 1.19 0.088 2034 C21 14824849 rs2822753 G 0.357 10631 2.41E−03 1.13 0.386 1700 4.57E−03 1.11 0.382 2034 C16 53995959 rs1033043 T 0.574 10635 2.41E−03 1.13 0.604 1700 1.67E−02 1.09 0.596 2034 C09 33091838 rs10758186 G 0.381 10633 2.41E−03 1.13 0.41 1700 5.48E−03 1.11 0.406 2034 C08 125394399 rs4620270 T 0.13 10627 2.42E−03 1.19 0.15 1699 8.40E−04 1.19 0.151 2033 C01 69518464 rs10489554 T 0.77 10633 2.42E−03 1.16 0.795 1700 4.45E−03 1.13 0.792 2034 C01 153811448 rs12567958 C 0.266 10615 2.42E−03 1.14 0.293 1700 7.12E−03 1.12 0.288 2034 C04 17086471 rs7442366 T 0.821 10635 2.42E−03 1.17 0.844 1700 4.54E−04 1.19 0.845 2034 C07 99312573 rs999885 T 0.498 10467 2.43E−03 1.13 0.528 1678 4.30E−03 1.11 0.524 2012 C03 61747598 rs603052 T 0.778 10629 2.43E−03 1.16 0.802 1700 4.06E−03 1.14 0.799 2034 C07 72804700 rs7787362 C 0.557 10628 2.43E−03 1.13 0.587 1700 1.23E−02 1.1 0.58 2034 C06 79723924 rs1338023 T 0.623 10465 2.43E−03 1.13 0.652 1647 3.54E−03 1.12 0.649 1975 C05 667701 rs1697952 C 0.368 10612 2.43E−03 1.13 0.397 1697 4.73E−03 1.11 0.393 2030 C17 40648038 rs1122326 C 0.241 10633 2.44E−03 1.15 0.267 1700 3.93E−03 1.13 0.264 2034 C10 10412081 rs10508403 T 0.091 10635 2.44E−03 1.22 0.109 1700 2.93E−02 1.14 0.103 2034 C02 171512196 rs1837241 A 0.697 10634 2.44E−03 1.14 0.724 1700 1.28E−03 1.14 0.724 2034 C06 17345030 rs6940891 C 0.169 10635 2.45E−03 1.17 0.192 1700 2.87E−03 1.15 0.19 2034 C06 42287224 rs713383 G 0.684 10635 2.45E−03 1.14 0.712 1700 4.07E−03 1.12 0.708 2034 C12 121500993 rs7979863 A 0.375 10630 2.46E−03 1.13 0.404 1700 2.05E−03 1.12 0.402 2034 C06 37577310 rs9380681 C 0.308 10635 2.46E−03 1.14 0.335 1700 2.37E−03 1.13 0.333 2034 C17 77817713 rs17674253 A 0.579 10632 2.46E−03 1.13 0.608 1698 7.85E−03 1.1 0.603 2032 C01 113140463 rs773586 A 0.483 10633 2.46E−03 1.13 0.513 1700 3.45E−04 1.14 0.515 2034 C06 92200200 rs6454860 G 0.325 10314 2.46E−03 1.14 0.353 1639 3.16E−03 1.12 0.35 1969 C10 61460650 rs4948410 A 0.784 10631 2.47E−03 1.16 0.808 1700 4.52E−03 1.14 0.805 2034 C06 157865565 rs16900254 A 0.408 10635 2.47E−03 1.13 0.437 1700 1.34E−02 1.1 0.43 2034 C15 93466050 rs176656 A 0.09 10635 2.48E−03 1.22 0.108 1700 6.94E−04 1.23 0.109 2034 C11 102978426 rs719527 C 0.233 10612 2.49E−03 1.15 0.258 1700 5.40E−03 1.13 0.254 2034 C20 57627978 rs6128327 A 0.64 10481 2.50E−03 1.13 0.668 1683 1.61E−03 1.13 0.667 2015 C07 21751434 rs1174943 G 0.155 10631 2.51E−03 1.17 0.176 1700 1.20E−02 1.13 0.171 2034 C07 8617064 rs917038 C 0.784 10591 2.51E−03 1.16 0.808 1689 2.80E−02 1.1 0.8 2023 C20 22311552 rs199812 C 0.886 10635 2.51E−03 1.22 0.904 1700 9.30E−04 1.22 0.904 2034 C04 147576738 rs2241521 A 0.234 10634 2.51E−03 1.15 0.26 1700 1.05E−02 1.11 0.254 2034 C11 20014361 rs920671 A 0.182 10634 2.51E−03 1.16 0.205 1700 2.83E−03 1.15 0.203 2034 C11 82788837 rs4623925 A 0.267 10633 2.51E−03 1.14 0.294 1700 2.34E−02 1.1 0.286 2034 C21 24056599 rs2828515 G 0.122 10633 2.52E−03 1.19 0.142 1700 8.56E−04 1.2 0.143 2034 C02 44054859 rs6709904 A 0.907 10635 2.52E−03 1.24 0.924 1700 1.38E−03 1.24 0.924 2034 C17 21252111 rs9911448 C 0.962 10635 2.52E−03 1.41 0.972 1700 5.90E−03 1.33 0.971 2034 C18 55909735 rs9948303 G 0.099 10635 2.52E−03 1.21 0.117 1700 1.15E−03 1.21 0.117 2034 C01 20385176 rs2072671 C 0.314 10635 2.53E−03 1.13 0.341 1700 8.33E−04 1.14 0.342 2034 C01 113074488 rs6688859 T 0.68 10635 2.53E−03 1.14 0.708 1700 2.92E−04 1.15 0.711 2034 C15 95693327 rs7177625 G 0.683 10633 2.53E−03 1.14 0.71 1700 9.07E−03 1.11 0.705 2033 C12 20118148 rs11045018 G 0.749 10626 2.53E−03 1.15 0.774 1699 5.07E−04 1.16 0.776 2033 C16 82538999 rs1870843 T 0.599 10633 2.53E−03 1.13 0.628 1700 2.99E−03 1.12 0.625 2034 C01 78369472 rs1543675 C 0.376 10633 2.53E−03 1.13 0.405 1700 1.08E−02 1.1 0.399 2034 C01 107498557 rs2335793 C 0.887 10628 2.53E−03 1.22 0.905 1698 8.13E−04 1.23 0.906 2031 C03 6741178 rs978658 G 0.611 10635 2.54E−03 1.13 0.639 1700 1.13E−03 1.13 0.639 2034 C05 76843306 rs690280 T 0.422 10580 2.54E−03 1.13 0.451 1694 8.75E−03 1.1 0.446 2028 C10 30821283 rs7086224 A 0.418 10633 2.54E−03 1.13 0.448 1700 4.77E−03 1.11 0.444 2034 C07 86648971 rs2373593 A 0.862 10635 2.55E−03 1.2 0.882 1700 4.51E−03 1.17 0.88 2034 C19 53768499 rs3760802 A 0.499 10633 2.55E−03 1.13 0.528 1699 3.62E−03 1.11 0.525 2033 C17 40663717 rs12603327 C 0.241 10632 2.55E−03 1.15 0.267 1700 4.05E−03 1.13 0.264 2034 C10 101886011 rs1539089 C 0.222 10635 2.55E−03 1.15 0.247 1700 1.13E−02 1.12 0.241 2034 C19 8795907 rs10406508 T 0.764 10635 2.56E−03 1.15 0.789 1700 2.84E−02 1.1 0.78 2034 C05 50786999 rs1423611 C 0.445 10631 2.56E−03 1.13 0.474 1700 5.58E−03 1.11 0.47 2034 C05 50786999 rs1423611 C 0.445 10631 2.56E−03 1.13 0.474 1700 5.58E−03 1.11 0.47 2034 C06 29574824 rs1345227 G 0.379 10630 2.57E−03 1.13 0.408 1700 4.62E−03 1.11 0.404 2034 C02 172857641 rs6758704 T 0.709 10633 2.57E−03 1.14 0.736 1700 4.05E−03 1.12 0.733 2034 C05 9699750 rs2106687 G 0.125 10631 2.58E−03 1.19 0.146 1700 6.01E−03 1.16 0.142 2033 C22 19683076 rs430305 T 0.828 10635 2.58E−03 1.18 0.85 1700 2.96E−03 1.16 0.848 2034 C19 22695812 rs4933027 T 0.085 10634 2.58E−03 1.22 0.102 1700 9.19E−03 1.18 0.099 2034 C11 83108627 rs7952084 A 0.357 10635 2.58E−03 1.13 0.386 1700 5.81E−03 1.11 0.382 2034 C07 27992355 rs10225945 A 0.846 10535 2.59E−03 1.19 0.867 1697 4.58E−03 1.16 0.865 2030 C04 10063925 rs714086 G 0.759 10631 2.59E−03 1.15 0.784 1700 1.36E−02 1.11 0.778 2033 C08 138245904 rs4451334 A 0.062 10632 2.59E−03 1.26 0.077 1698 7.62E−03 1.21 0.074 2032 C05 115396824 rs9326981 C 0.949 10634 2.59E−03 1.34 0.961 1700 3.01E−03 1.3 0.96 2034 C10 101903540 rs11190578 T 0.222 10631 2.59E−03 1.15 0.247 1700 1.15E−02 1.12 0.241 2034 C10 102146771 rs4630219 C 0.099 10572 2.60E−03 1.21 0.117 1696 2.90E−03 1.19 0.115 2027 C17 40667190 rs7214921 C 0.241 10634 2.60E−03 1.15 0.267 1700 4.13E−03 1.13 0.264 2034 C14 64300426 rs12433694 C 0.479 10635 2.61E−03 1.13 0.509 1700 1.43E−02 1.09 0.501 2034 C22 18282773 rs1978058 T 0.376 10630 2.61E−03 1.13 0.404 1700 1.08E−02 1.1 0.398 2033 C04 131671262 rs1027884 T 0.497 10634 2.61E−03 1.13 0.527 1700 2.40E−03 1.12 0.525 2034 C08 28224848 rs904053 G 0.225 10634 2.61E−03 1.15 0.25 1700 3.98E−02 1.09 0.24 2034 C08 28224848 rs904053 G 0.225 10634 2.61E−03 1.15 0.25 1700 3.98E−02 1.09 0.24 2034 C16 54000987 rs2665282 A 0.574 10607 2.61E−03 1.13 0.603 1696 1.79E−02 1.09 0.596 2030 C05 136028429 rs4141140 G 0.7 10632 2.62E−03 1.14 0.727 1700 1.58E−02 1.1 0.721 2034 C07 49507399 rs13240380 T 0.434 10632 2.62E−03 1.13 0.463 1700 1.78E−03 1.12 0.462 2033 C09 11743695 rs10960174 G 0.613 10629 2.62E−03 1.13 0.641 1698 1.74E−03 1.13 0.64 2031 C15 43706836 rs7172161 G 0.513 10634 2.62E−03 1.13 0.543 1700 2.59E−03 1.12 0.541 2034 C04 162740637 rs9942159 T 0.377 10550 2.63E−03 1.13 0.406 1691 2.09E−03 1.12 0.404 2024 C05 158736740 rs1433048 G 0.192 10317 2.63E−03 1.16 0.216 1652 1.82E−02 1.11 0.21 1981 C10 84886235 rs4411234 C 0.638 10631 2.63E−03 1.13 0.666 1700 2.14E−04 1.15 0.67 2034 C12 100468481 rs864302 T 0.483 10630 2.63E−03 1.13 0.512 1700 7.50E−03 1.1 0.507 2034 C05 76657043 rs251421 C 0.26 10618 2.64E−03 1.14 0.286 1690 5.58E−03 1.12 0.283 2023 C07 46531242 rs6956126 G 0.885 10632 2.64E−03 1.22 0.904 1700 2.41E−03 1.2 0.903 2034 C09 129104520 rs7026302 G 0.908 10633 2.64E−03 1.24 0.924 1700 2.87E−02 1.15 0.919 2034 C11 121657794 rs531743 A 0.954 10633 2.64E−03 1.36 0.966 1700 2.00E−03 1.34 0.965 2034 C11 33462777 rs10836066 T 0.301 10634 2.65E−03 1.14 0.328 1700 3.03E−02 1.09 0.319 2034 C05 122595829 rs9327287 G 0.262 10632 2.65E−03 1.14 0.288 1700 7.19E−03 1.12 0.284 2034 C04 181363537 rs17090640 G 0.952 10635 2.65E−03 1.35 0.964 1700 1.64E−02 1.24 0.961 2034 C04 119551429 rs6820367 A 0.35 10634 2.65E−03 1.13 0.379 1700 4.66E−03 1.11 0.375 2034 C19 62070079 rs8113561 G 0.954 10625 2.65E−03 1.36 0.966 1700 3.66E−02 1.21 0.962 2034 C08 97162902 rs2440213 A 0.358 10632 2.65E−03 1.13 0.387 1700 5.98E−03 1.11 0.383 2033 C10 93013669 rs1028935 A 0.185 10633 2.65E−03 1.16 0.208 1700 1.86E−03 1.15 0.207 2034 C06 24562175 rs9393558 T 0.347 10635 2.65E−03 1.13 0.375 1700 2.11E−02 1.09 0.367 2034 C09 103242888 rs7854755 A 0.198 10589 2.65E−03 1.16 0.222 1694 7.15E−03 1.13 0.218 2027 C09 79420643 rs10867740 C 0.236 10625 2.65E−03 1.15 0.262 1699 2.00E−03 1.14 0.261 2033 C20 53952228 rs6068930 G 0.039 10620 2.66E−03 1.32 0.051 1700 9.79E−03 1.26 0.049 2034 C14 68370111 rs1291302 C 0.259 10527 2.66E−03 1.14 0.285 1675 3.98E−03 1.13 0.282 2008 C01 93943749 rs4147861 G 0.923 10526 2.66E−03 1.27 0.939 1668 2.12E−03 1.25 0.938 2000 C14 98178185 rs2273840 A 0.931 10569 2.67E−03 1.28 0.945 1677 1.07E−03 1.29 0.945 2009 C14 98178185 rs2273840 A 0.931 10569 2.67E−03 1.28 0.945 1677 1.07E−03 1.29 0.945 2009 CX 138713457 rs1948488 A 0.223 8219 2.68E−03 1.19 0.254 1094 4.52E−03 1.16 0.25 1307 C12 20196656 rs7299937 T 0.059 10635 2.68E−03 1.26 0.074 1700 7.12E−03 1.22 0.071 2034 C04 87630493 rs10516770 T 0.055 10635 2.69E−03 1.27 0.069 1700 4.44E−03 1.24 0.067 2034 C02 172822314 rs4668412 A 0.709 10634 2.69E−03 1.14 0.736 1700 4.24E−03 1.12 0.733 2034 C06 36770559 rs236444 T 0.253 10634 2.70E−03 1.14 0.279 1700 3.68E−04 1.16 0.281 2034 C11 103253198 rs10502020 G 0.446 10634 2.71E−03 1.13 0.476 1700 8.02E−03 1.1 0.47 2034 C04 131653392 rs4383635 A 0.491 10630 2.71E−03 1.13 0.521 1699 2.25E−03 1.12 0.519 2033 C04 87557966 rs2199309 C 0.229 10234 2.71E−03 1.15 0.255 1653 8.94E−04 1.15 0.256 1977 C09 23737791 rs1329044 C 0.153 10631 2.71E−03 1.17 0.175 1700 6.15E−04 1.18 0.176 2034 C12 127797687 rs470477 T 0.311 10632 2.71E−03 1.13 0.338 1700 5.14E−03 1.12 0.334 2033 C13 105492839 rs1927771 A 0.411 10633 2.72E−03 1.13 0.44 1700 4.66E−03 1.11 0.436 2034 CX 4916022 rs6638525 C 0.107 8269 2.73E−03 1.25 0.13 1103 1.91E−03 1.24 0.129 1316 C09 134921961 rs2297538 G 0.73 10630 2.75E−03 1.15 0.756 11700 5.61E−03 1.12 0.752 2034 C11 68645465 rs2924536 A 0.447 10631 2.75E−03 1.13 0.476 1700 1.83E−02 1.09 0.469 2034 C02 173022859 rs10165126 C 0.705 10630 2.75E−03 1.14 0.732 1699 2.98E−03 1.13 0.729 2033 C11 10906227 rs10500734 A 0.767 10617 2.75E−03 1.15 0.791 1692 2.25E−02 1.11 0.784 2025 C02 12183852 rs10929777 C 0.3 10634 2.75E−03 1.14 0.327 1700 7.76E−03 1.11 0.323 2034 C01 106549733 rs10494048 T 0.387 10589 2.75E−03 1.13 0.416 1699 2.94E−02 1.08 0.406 2030 C10 69228609 rs17456902 G 0.872 10635 2.76E−03 1.2 0.891 1700 3.98E−03 1.18 0.889 2034 C04 90099908 rs2924936 G 0.869 10635 2.76E−03 1.2 0.888 1700 3.77E−04 1.22 0.89 2034 C06 37561316 rs9296225 C 0.472 10635 2.76E−03 1.13 0.502 1700 3.40E−03 1.11 0.499 2034 C22 17337894 rs2019061 T 0.685 10621 2.77E−03 1.14 0.712 1694 6.23E−03 1.12 0.708 2028 C02 16792100 rs11897395 C 0.889 10590 2.77E−03 1.22 0.907 1686 1.35E−02 1.16 0.903 2020 C02 43918060 rs1991739 A 0.619 10632 2.77E−03 1.13 0.647 1700 1.72E−02 1.09 0.64 2034 C07 102594288 rs7804867 A 0.205 10634 2.78E−03 1.15 0.229 1700 1.92E−03 1.15 0.228 2034 C06 10170597 rs6459613 A 0.545 10601 2.78E−03 1.13 0.574 1698 2.65E−02 1.09 0.565 2030 C05 50904720 rs7708362 T 0.345 10619 2.78E−03 1.13 0.373 1687 5.55E−03 1.11 0.369 2021 C05 94682297 rs464906 C 0.614 10630 2.78E−03 1.13 0.642 1700 9.79E−03 1.1 0.637 2034 C10 8311160 rs1419294 T 0.711 10635 2.78E−03 1.14 0.738 1700 1.09E−03 1.14 0.738 2034 C10 2108862 rs12776254 G 0.167 10634 2.78E−03 1.17 0.19 1700 1.95E−03 1.16 0.189 2034 C20 59771295 rs6128843 T 0.182 10634 2.79E−03 1.16 0.206 1700 1.16E−03 1.16 0.206 2034 C02 242432072 rs12052982 A 0.958 10630 2.79E−03 1.38 0.969 1698 7.24E−03 1.3 0.967 2032 C10 102016372 rs9420802 G 0.209 10632 2.80E−03 1.15 0.233 1698 1.15E−02 1.12 0.228 2032 C07 149980541 rs10277774 C 0.383 10632 2.80E−03 1.13 0.412 1699 1.84E−03 1.12 0.411 2033 C12 21065184 rs1910186 C 0.109 10630 2.80E−03 1.2 0.128 1700 1.84E−03 1.19 0.128 2034 C12 21065184 rs1910186 C 0.109 10630 2.80E−03 1.2 0.128 1700 1.84E−03 1.19 0.128 2034 C17 73745676 rs1000299 A 0.055 10635 2.81E−03 1.27 0.069 1700 2.50E−02 1.19 0.064 2034 C06 162143621 rs7739802 T 0.491 10594 2.81E−03 1.12 0.521 1699 4.70E−04 1.14 0.523 2030 C11 102072274 rs1276252 G 0.252 10634 2.81E−03 1.14 0.277 1700 1.08E−02 1.11 0.272 2034 C12 123335210 rs3759107 T 0.127 10635 2.81E−03 1.19 0.147 1700 3.67E−03 1.17 0.145 2034 C11 42941748 rs7939657 T 0.558 10632 2.81E−03 1.13 0.587 1700 3.56E−03 1.11 0.585 2034 C14 63855666 rs7147624 G 0.798 10635 2.81E−03 1.16 0.821 1700 3.48E−03 1.15 0.819 2034 C07 21959042 rs17146355 A 0.05 10619 2.82E−03 1.29 0.063 1697 1.93E−03 1.28 0.063 2031 C01 7589173 rs10462018 C 0.816 10632 2.82E−03 1.17 0.839 1700 1.67E−02 1.12 0.833 2034 C15 87930503 rs12595195 C 0.275 10632 2.82E−03 1.14 0.301 1700 5.15E−03 1.12 0.298 2034 C04 90107239 rs13130 T 0.87 10623 2.82E−03 1.2 0.889 1698 3.57E−04 1.22 0.891 2032 C03 99664143 rs1531377 T 0.173 10628 2.83E−03 1.16 0.196 1699 1.02E−02 1.13 0.191 2033 C04 30136639 rs2060515 T 0.111 10569 2.83E−03 1.2 0.13 1689 4.85E−03 1.17 0.127 2020 C18 58447316 rs2332575 A 0.053 10634 2.84E−03 1.28 0.066 1699 2.85E−03 1.26 0.065 2033 C06 12338790 rs1028716 T 0.06 10632 2.84E−03 1.26 0.074 1700 4.77E−03 1.23 0.072 2034 C05 55657524 rs32496 C 0.573 10633 2.85E−03 1.13 0.601 1700 4.48E−03 1.11 0.598 2034 C08 5835084 rs890014 C 0.757 10635 2.86E−03 1.15 0.781 1700 4.61E−03 1.13 0.779 2034 C21 14821123 rs2822744 A 0.157 10633 2.86E−03 1.17 0.179 1700 4.96E−03 1.15 0.176 2034 C06 19958854 rs6905466 T 0.327 10635 2.86E−03 1.13 0.355 1700 1.18E−03 1.13 0.355 2034 C15 77441636 rs4255747 G 0.668 10635 2.86E−03 1.13 0.695 1700 1.01E−02 1.11 0.69 2034 C15 53381369 rs8041044 C 0.914 10627 2.86E−03 1.25 0.93 1698 1.09E−02 1.19 0.927 2032 C02 24312396 rs10200481 A 0.106 10635 2.86E−03 1.2 0.125 1700 1.22E−02 1.15 0.121 2033 C10 16380276 rs2184383 G 0.805 10628 2.87E−03 1.16 0.828 1700 4.18E−03 1.14 0.825 2034 C09 8506194 rs10119236 A 0.294 10632 2.87E−03 1.14 0.321 1700 2.66E−02 1.09 0.312 2034 C02 78341614 rs2861264 T 0.105 10635 2.87E−03 1.2 0.123 1700 3.16E−03 1.18 0.122 2034 C18 58394216 rs3744927 G 0.773 10634 2.88E−03 1.15 0.797 1700 1.35E−02 1.12 0.792 2034 C02 77756026 rs6547152 C 0.787 10620 2.89E−03 1.16 0.811 1698 1.38E−03 1.16 0.811 2032 C12 52445647 rs6580960 A 0.541 10635 2.89E−03 1.13 0.57 1700 3.40E−03 1.11 0.567 2034 C07 27780647 rs740127 G 0.595 10635 2.89E−03 1.13 0.624 1700 1.23E−02 1.1 0.618 2034 C07 50816853 rs17134122 A 0.966 10634 2.89E−03 1.43 0.976 1700 1.10E−02 1.32 0.974 2034 C22 34868465 rs132717 C 0.62 10359 2.90E−03 1.13 0.648 1664 2.36E−02 1.09 0.64 1990 C18 55211067 rs8088514 C 0.461 10602 2.90E−03 1.12 0.49 1693 1.65E−02 1.09 0.482 2027 C10 119681455 rs7922488 G 0.533 10616 2.90E−03 1.13 0.562 1692 4.75E−03 1.11 0.558 2026 C05 158745072 rs7709212 T 0.678 10635 2.90E−03 1.14 0.705 1700 1.55E−02 1.1 0.699 2034 C05 23761851 rs11743379 T 0.507 10633 2.91E−03 1.12 0.536 1700 4.46E−04 1.14 0.539 2034 C06 130039640 rs376632 G 0.89 10633 2.91E−03 1.22 0.908 1699 2.60E−03 1.2 0.907 2033 C10 8277669 rs4747760 G 0.875 10631 2.91E−03 1.2 0.894 1700 3.50E−03 1.18 0.892 2034 C03 145966921 rs13061557 T 0.699 10630 2.91E−03 1.14 0.726 1700 1.57E−02 1.1 0.719 2034 C06 122997014 rs9388117 A 0.671 10616 2.92E−03 1.13 0.698 1699 1.83E−02 1.1 0.691 2033 C10 132443494 rs893504 C 0.071 10635 2.92E−03 1.24 0.087 1700 2.64E−03 1.22 0.086 2034 C04 40312795 rs4447895 C 0.888 10634 2.92E−03 1.22 0.906 1700 1.56E−03 1.21 0.906 2034 C06 162147237 rs3016536 G 0.517 10635 2.93E−03 1.12 0.546 1700 1.72E−03 1.12 0.545 2034 C15 58046702 rs4775234 C 0.259 10530 2.93E−03 1.14 0.285 1681 3.63E−02 1.09 0.276 2009 C10 107117270 rs11192557 T 0.876 10623 2.93E−03 1.2 0.895 1698 2.56E−03 1.19 0.893 2032 C07 1681599 rs10267593 G 0.835 10635 2.93E−03 1.18 0.856 1700 2.02E−04 1.21 0.859 2034 C14 98123983 rs2895811 C 0.448 10607 3.04E−03 1.12 0.478 1694 3.73E−03 1.11 0.475 2027 C17 18260758 rs854771 C 0.554 10635 3.18E−03 1.12 0.583 1700 1.54E−03 1.12 0.583 2034 C04 129890119 rs4549394 T 0.097 10631 3.31E−03 1.21 0.115 1700 2.25E−03 1.2 0.114 2034 C02 176994186 rs12621733 G 0.899 10634 3.47E−03 1.22 0.916 1700 9.37E−04 1.24 0.917 2034 C01 113692475 rs1217407 A 0.249 10631 3.56E−03 1.14 0.274 1700 1.20E−03 1.14 0.275 2034 C02 36037410 rs10203034 A 0.68 10634 3.64E−03 1.13 0.706 1700 2.27E−03 1.13 0.706 2034 C01 113628929 rs2797409 C 0.249 10634 3.79E−03 1.14 0.274 1700 1.29E−03 1.14 0.275 2034 C12 69325443 rs7978668 T 0.918 10635 3.84E−03 1.25 0.933 1700 1.61E−03 1.25 0.933 2034 C12 69326403 rs767760 A 0.914 10635 3.96E−03 1.24 0.93 1700 1.10E−03 1.25 0.93 2034 C12 69368222 rs949664 A 0.863 10632 3.98E−03 1.19 0.882 1700 1.46E−03 1.19 0.882 2034 C12 69340682 rs7309888 C 0.794 10631 4.11E−03 1.15 0.816 1700 1.40E−03 1.16 0.817 2034 C14 98160936 rs12435918 G 0.333 10635 4.43E−03 1.12 0.36 1700 2.64E−03 1.12 0.359 2034 C07 11669876 rs2355129 A 0.362 10635 4.59E−03 1.12 0.389 1699 1.13E−03 1.13 0.391 2033 C08 129057022 rs2648896 C 0.149 10633 5.75E−03 1.16 0.169 1700 2.49E−03 1.16 0.169 2034 C12 69347673 rs7976576 T 0.794 10635 6.31E−03 1.15 0.816 1700 2.22E−03 1.15 0.816 2034 C07 11658292 rs10215881 C 0.494 10630 8.18E−03 1.11 0.52 1699 1.88E−03 1.12 0.523 2033 C12 124462726 rs7310042 G 0.193 10634 8.35E−03 1.14 0.214 1700 2.55E−03 1.15 0.215 2034 C07 11646149 rs6460851 G 0.288 10624 8.43E−03 1.12 0.312 1698 1.88E−03 1.13 0.314 2031 C02 128444077 rs46627431 T 0.515 10622 1.30E−02 1.1 0.539 1700 2.49E−03 1.12 0.543 2034

TABLE 2 Association results for the Icelandic discovery cohorts, and the replication cohorts. The columns in the table indicate (1) the cohort, (2) rs name of the marker in question, (3) the chromosome, (4) position of the marker in NCBI Build 34, (5) p-value of the association, (6) the Relative Risk of the association, (7) the number of MI patients, (8) the frequency of the associating allele in patients, (9) the number of controls, (10) the frequency of the associating allele in controls, (11) the associating allele. Cohort rs-name chr position p-value RR Naff f (aff) Ncon f (con) allele SG01S1480 C01 57254228 Iceland discovery group rs2991515 0.001045 1.14 1642 0.514 6868 0.480 T Iceland replication group rs2991515 0.054380 1.13 560 0.507 3393 0.476 T Iceland All rs2991515 0.000108 1.14 2202 0.512 10261 0.479 T Philadelphia NA Atlanta NA Durham NA All US groups NA NA NA All replication groups 0.054379 1.13 544 T All groups 0.000108 1.14 2016 T SG01S1340 C01 113676295 Iceland discovery group rs2476601 0.000452 1.23 1632 0.156 6858 0.130 A Iceland replication group rs2476601 0.001253 1.34 562 0.167 3393 0.130 A Iceland All rs2476601 0.000003 1.26 2194 0.159 10251 0.130 A Philadelphia NA Atlanta NA Durham rs2476601 0.407813 1.12 932 0.095 544 0.086 A All US groups 0.407813 1.1164 932 A All replication groups 0.001741 1.2678 1478 A All groups 0.000003 1.2404 2941 A SG02S870 C02 36022756 Iceland discovery group rs6747236 0.004309 1.14 1634 0.743 6863 0.717 T Iceland replication group rs6747236 0.101400 1.13 544 0.741 3391 0.717 T Iceland All rs6747236 0.000905 1.14 2178 0.742 10254 0.717 T Philadelphia NA Atlanta NA Durham NA All US groups NA NA NA All replication groups 0.101403 1.13 528 T All groups 0.000905 1.14 1994 T SG02S840 C02 176947426 Iceland discovery group rs921083 0.000163 1.21 1642 0.806 6867 0.774 G Iceland replication group rs921083 0.054180 1.17 549 0.805 3392 0.779 G Iceland All rs921083 0.000025 1.20 2191 0.806 10259 0.776 G Philadelphia NA Atlanta NA Durham NA All US groups NA NA NA All replication groups 0.054178 1.17 533 G All groups 0.000025 1.20 2006 G SG02S832 C02 212588265 Iceland discovery group rs12329252 0.000680 1.16 1641 0.710 6868 0.677 T Iceland replication group rs12329252 0.327900 1.07 554 0.692 3393 0.677 T Iceland All rs12329252 0.000500 1.14 2195 0.705 10261 0.677 T Philadelphia NA Atlanta NA Durham NA All US groups NA NA NA All replication groups 0.327938 1.07 538 T All groups 0.000500 1.14 2010 T SG03S670 C03 62420156 Iceland discovery group rs9874646 0.000330 1.18 1642 0.746 6867 0.713 T Iceland replication group rs9874646 0.173800 1.10 555 0.721 3393 0.700 T Iceland All rs9874646 0.000078 1.17 2197 0.739 10260 0.709 T Philadelphia NA Atlanta NA Durham NA All US groups NA NA NA All replication groups 0.173753 1.10 539 T All groups 0.000078 1.17 2012 T SG03S671 C03 191533619 Iceland discovery group rs9864293 0.007956 1.12 1624 0.418 6866 0.391 C Iceland replication group rs9864293 0.143800 1.22 119 0.424 3392 0.377 C Iceland All rs9864293 0.000591 1.14 1743 0.419 10258 0.386 C Philadelphia NA Atlanta NA Durham NA All US groups NA NA NA All replication groups 0.143805 1.22 115 C All groups 0.000591 1.14 1596 C SG04S816 C04 21568604 Iceland discovery group rs4282162 0.000562 1.15 1641 0.565 6867 0.529 T Iceland replication group rs4282162 0.221000 1.08 559 0.547 3393 0.527 T Iceland All rs4282162 0.000244 1.14 2200 0.560 10260 0.528 T Philadelphia NA Atlanta NA Durham NA All US groups NA NA NA All replication groups 0.221045 1.08 543 T All groups 0.000244 1.14 2014 T SG04S820 C04 45948792 Iceland discovery group rs7661204 0.034390 1.09 1641 0.576 6868 0.555 C Iceland replication group rs7661204 0.026880 1.16 562 0.583 3393 0.547 C Iceland All rs7661204 0.002633 1.11 2203 0.578 10261 0.552 C Philadelphia NA Atlanta NA Durham NA All US groups NA NA NA All replication groups 0.026881 1.16 546 C All groups 0.002633 1.11 2017 C SG05S3061 C05 118135750 Iceland discovery group rs728676 0.003297 1.13 1641 0.470 6868 0.440 T Iceland replication group rs728676 0.011820 1.18 561 0.482 3392 0.441 T Iceland All rs728676 0.000145 1.14 2202 0.473 10260 0.440 T Philadelphia NA Atlanta rs728676 0.101514 1.14 464 0.498 1012 0.465 T Durham rs728676 0.596462 0.97 1168 0.484 718 0.493 T All US groups 0.513855 1.03 1632 T All replication groups 0.038993 1.09 2177 T All groups 0.000449 1.11 3648 T SG05S3058 C05 158504417 Iceland discovery group rs7442701 0.000114 1.22 1625 0.208 6865 0.176 T Iceland replication group rs7442701 0.913600 1.02 120 0.175 3390 0.172 T Iceland All rs7442701 0.000045 1.22 1745 0.205 10255 0.175 T Philadelphia NA Atlanta NA Durham NA All US groups NA NA NA All replication groups 0.913822 1.02 116 T All groups 0.000045 1.22 1598 T SG06S1298 C06 29516393 Iceland discovery group rs2074464 0.002492 1.13 1633 0.475 6862 0.444 T Iceland replication group rs2074464 0.191700 1.09 545 0.466 3390 0.445 T Iceland All rs2074464 0.000945 1.12 2178 0.473 10252 0.444 T Philadelphia NA Atlanta rs2074464 0.076812 1.18 365 0.484 576 0.442 T Durham rs2074464 0.290169 1.07 1200 0.469 728 0.451 T All US groups 0.059737 1.11 1565 T All replication groups 0.022395 1.10 2094 T All groups 0.000145 1.12 3559 T SG07S302 C07 116579323 Iceland discovery group rs1029396 0.001065 1.28 1634 0.089 6867 0.071 G Iceland replication group rs1029396 0.719800 0.95 548 0.063 3393 0.066 G Iceland All rs1029396 0.003796 1.21 2182 0.082 10260 0.069 G Philadelphia NA Atlanta rs1029396 0.391029 1.15 363 0.094 572 0.082 G Durham rs1029396 0.053907 1.25 1212 0.101 735 0.083 G All US groups 0.038030 1.22 1575 G All replication groups 0.138284 1.12 2107 G All groups 0.000370 1.21 3573 G SG08S1314 C08 18899082 Iceland discovery group rs334198 0.020830 1.19 1630 0.090 6865 0.076 A Iceland replication group rs334198 0.059380 1.25 549 0.089 3393 0.073 A Iceland All rs334198 0.002535 1.21 2179 0.089 10258 0.075 A Philadelphia rs334198 0.370833 0.87 543 0.088 475 0.100 A Atlanta rs334198 0.778416 1.05 367 0.086 542 0.082 A Durham NA All US groups 0.627319 0.95 910 A All replication groups 0.348780 1.08 1443 A All groups 0.016141 1.14 2905 A SG08S1315 C08 28215758 Iceland discovery group rs4732849 0.000349 1.18 1641 0.306 6868 0.273 T Iceland replication group rs4732849 0.077900 1.14 550 0.298 3393 0.272 T Iceland All rs4732849 0.000056 1.17 2191 0.304 10261 0.273 T Philadelphia NA Atlanta NA Durham NA All US groups NA NA NA All replication groups 0.077897 1.14 534 T All groups 0.000056 1.17 2006 T SG08S1325 C08 129065286 Iceland discovery group rs2302793 0.002452 1.14 1614 0.462 6846 0.431 G Iceland replication group rs2302793 0.601500 1.09 87 0.454 3370 0.434 G Iceland All rs2302793 0.001920 1.13 1701 0.461 10216 0.432 G Philadelphia NA Atlanta NA Durham NA All US groups NA NA NA All replication groups 0.601476 1.09 84 G All groups 0.001920 1.13 1557 G SG08S1326 C08 129067370 Iceland discovery group rs3931282 0.001650 1.14 1634 0.461 6868 0.428 C Iceland replication group rs3931282 0.050490 1.14 547 0.463 3393 0.431 C Iceland All rs3931282 0.000216 1.14 2181 0.461 10261 0.429 C Philadelphia NA Atlanta rs3931282 0.205449 0.89 362 0.438 587 0.468 C Durham rs3931282 0.208270 0.92 1196 0.455 732 0.476 C All US groups 0.078904 0.91 1558 C All replication groups 0.904130 0.99 2089 C All groups 0.030734 1.07 3555 C SG10S822 C10 45239070 Iceland discovery group rs2279434 0.000031 1.38 1634 0.088 6868 0.065 T Iceland replication group rs2279434 0.509900 1.09 544 0.071 3392 0.065 T Iceland All rs2279434 0.000053 1.31 2178 0.083 10260 0.065 T Philadelphia rs2279434 0.81 532 0.081 472 0.097 T Atlanta rs2279434 0.83 362 0.070 513 0.084 T Durham NA All US groups 0.096180 0.82 894 T All replication groups 0.422694 0.93 1422 T All groups 0.006627 1.17 2888 T SG10S314 C10 90667504 Iceland discovery group rs1412444 0.000082 1.18 1644 0.396 6861 0.357 A Iceland replication group rs1412444 0.312500 1.07 582 0.374 3389 0.358 A Iceland All rs1412444 0.000076 1.15 2226 0.390 10250 0.357 A Philadelphia NA Atlanta rs1412444 0.314043 1.11 367 0.356 581 0.333 A Durham rs1412444 0.913736 1.02 257 0.368 121 0.364 A All US groups 0.360084 1.08 624 A All replication groups 0.173888 1.07 1189 A All groups 0.000063 1.14 2662 A SG12S844 C12 21092930 Iceland discovery group rs11045689 0.011540 1.12 1630 0.321 6854 0.297 G Iceland replication group rs11045689 0.133900 1.11 541 0.318 3386 0.295 G Iceland All rs11045689 0.002878 1.12 2171 0.320 10240 0.296 G Philadelphia NA Atlanta NA Durham NA All US groups NA NA NA All replication groups 0.133868 1.11 526 G All groups 0.002878 1.12 1988 G SG14S801 C14 67308303 Iceland discovery group rs8003722 0.000343 1.26 1642 0.127 6867 0.104 A Iceland replication group rs8003722 0.007542 1.32 561 0.125 3393 0.098 A Iceland All rs8003722 0.000006 1.28 2203 0.126 10260 0.102 A Philadelphia NA Atlanta rs8003722 0.734831 1.04 472 0.151 1029 0.147 A Durham rs8003722 0.431112 0.93 1202 0.135 735 0.144 A All US groups 0.708199 0.97 1674 All replication groups 0.225792 1.08 2219 A All groups 0.000670 1.16 3691 A SG14S796 C14 98131730 Iceland discovery group rs7158073 0.000697 1.15 1630 0.461 6835 0.426 T Iceland replication group rs7158073 0.017800 1.17 546 0.477 3384 0.438 T Iceland All rs7158073 0.000055 1.15 2176 0.465 10219 0.430 T Philadelphia NA Atlanta rs7158073 0.647425 1.05 362 0.419 575 0.408 T Durham rs7158073 0.059831 1.14 1174 0.460 719 0.429 T All US groups 0.071211 1.10 1536 T All replication groups 0.003703 1.13 2066 T All groups 0.000012 1.14 3528 T SG14S794_SG14S795* C14 52400957 Iceland discovery group rs4444235 rs1957860 0.000323 0.84 1642 0.290 6868 0.326 C Iceland replication group rs4444235 rs1957860 0.015250 0.83 561 0.279 3393 0.317 C Iceland All rs4444235 rs1957860 0.000020 0.84 2203 0.287 10261 0.323 C Philadelphia NA Atlanta NA Durham NA All US groups NA NA NA All replication groups rs4444235 rs1957860 0.015245 0.83 545 C All groups rs4444235 rs1957860 0.000020 0.84 2017 C SG15S142 C15 24926452 Iceland discovery group rs2110209 0.001794 1.32 1634 0.063 6868 0.049 A Iceland replication group rs2110209 0.036840 1.36 545 0.059 3393 0.044 A Iceland All rs2110209 0.000106 1.34 2179 0.062 10261 0.047 A Philadelphia NA Atlanta NA Durham NA All US groups NA NA NA All replication groups 0.036835 1.36 529 A All groups 0.000105 1.34 1995 A SG17S742 C17 17934326 Iceland discovery group rs9902941 0.000041 1.19 1642 0.388 6867 0.348 C Iceland replication group rs9902941 0.961500 1.00 565 0.351 3393 0.351 C Iceland All rs9902941 0.000278 1.14 2207 0.379 10260 0.349 C Philadelphia rs9902941 0.170324 1.13 542 0.423 474 0.393 C Atlanta rs9902941 0.246078 1.09 591 0.372 1210 0.352 C Durham rs9902941 0.163124 1.10 1165 0.378 736 0.355 C All US groups 0.024495 1.10 2298 C All replication groups 0.055496 1.07 2847 C All groups 0.000023 1.13 4319 C SG17S743 C17 17943470 Iceland discovery group rs4925119 0.000093 1.18 1630 0.384 6857 0.345 A Iceland replication group rs4925119 0.975100 1.00 541 0.349 3384 0.349 A Iceland All rs4925119 0.000529 1.13 2171 0.375 10241 0.346 A Philadelphia rs4925119 0.312163 1.10 537 0.419 470 0.397 A Atlanta rs4925119 0.155471 1.11 646 0.372 1207 0.349 A Durham rs4925119 0.139467 1.11 1189 0.373 729 0.350 A All US groups 0.022416 1.10 2372 A All replication groups 0.051193 1.07 2898 A All groups 0.000037 1.12 4360 A SG17S744 C17 17947855 Iceland discovery group rs3183702 0.000036 1.19 1633 0.389 6866 0.348 T Iceland replication group rs3183702 0.970600 1.00 546 0.352 3391 0.351 T Iceland All rs3183702 0.000241 1.14 2179 0.380 10257 0.349 T Philadelphia rs3183702 0.132368 1.15 531 0.427 469 0.393 T Atlanta rs3183702 0.018991 1.26 362 0.391 539 0.337 T Durham rs3183702 0.469038 1.06 939 0.368 572 0.355 T All US groups 0.011987 1.14 1832 T All replication groups 0.041110 1.09 2362 T All groups 0.000009 1.14 3827 T SG17S746 C17 18035257 Iceland discovery group rs6502622 0.000128 1.18 1641 0.397 6868 0.359 G Iceland replication group rs6502622 0.699700 1.03 560 0.366 3393 0.360 G Iceland All rs6502622 0.000347 1.14 2201 0.389 10261 0.359 G Philadelphia rs6502622 0.277357 1.10 540 0.433 475 0.409 G Atlanta rs6502622 0.041642 1.16 593 0.401 1227 0.366 G Durham rs6502622 0.180470 1.10 1165 0.399 734 0.377 G All US groups 0.009300 1.12 2298 G All replication groups 0.016554 1.09 2842 G All groups 0.000010 1.13 4313 G SG17S750 C17 18149041 Iceland discovery group rs2955355 0.000393 1.17 1634 0.319 6868 0.285 C Iceland replication group rs2955355 0.393900 1.06 547 0.303 3393 0.290 C Iceland All rs2955355 0.000440 1.14 2181 0.315 10261 0.287 C Philadelphia rs2955355 0.630066 1.05 544 0.362 476 0.352 C Atlanta rs2955355 0.002362 1.37 360 0.360 534 0.291 C Durham NA All US groups 0.016778 1.18 904 C All replication groups 0.020472 1.12 1435 C All groups 0.000023 1.15 2901 C SG17S747 C17 18204411 Iceland discovery group rs854813 0.000154 1.17 1634 0.425 6865 0.387 C Iceland replication group rs854813 0.964800 1.00 543 0.386 3393 0.387 C Iceland All rs854813 0.000785 1.13 2177 0.415 10258 0.387 C Philadelphia rs854813 0.077440 1.17 520 0.468 462 0.429 C Atlanta rs854813 0.009373 1.29 364 0.449 539 0.388 C Durham NA All US groups 0.002182 1.23 884 C All replication groups 0.030822 1.11 1411 C All groups 0.000011 1.15 2877 C SG17S749 C17 18231090 Iceland discovery group rs854793 0.000495 1.19 1634 0.231 6865 0.201 A Iceland replication group rs854793 0.576100 0.95 491 0.198 3392 0.205 A Iceland All rs854793 0.004364 1.13 2125 0.223 10257 0.203 A Philadelphia rs854793 0.456629 1.08 505 0.260 454 0.246 A Atlanta rs854793 0.040285 1.26 369 0.255 539 0.213 A Durham NA All US groups 0.052002 1.16 874 A All replication groups 0.283691 1.06 1351 A All groups 0.000591 1.14 2820 A SG17S748 C17 18235585 Iceland discovery group rs854787 0.000005 1.21 1635 0.444 6816 0.398 C Iceland replication group rs854787 0.580200 0.96 565 0.390 3379 0.399 C Iceland all rs854787 0.000171 1.14 2200 0.430 10195 0.398 C Philadelphia rs854787 0.241799 1.11 542 0.458 475 0.433 C Atlanta rs854787 0.001746 1.36 360 0.475 507 0.399 C Durham NA All US groups 0.002955 1.22 902 C All replication groups 0.085873 1.08 1451 C All groups 0.000002 1.16 2916 C *2-marker haplotype consisting of markers SG14S794 and SG14S795

Example 2

Further genome-wide genotyping of Icelandic patients diagnosed with coronary artery disease and/or myocardial infarction was performed. Recruitment and phenotyping was described above under Example, and all methods involved were as described in the above.

Descriptions of the additional replication cohorts are as follows:

Cohort from Italy: The subjects from Verona were enrolled into the Verona Heart Project, which is an ongoing study aimed at identifying new risk factors for coronary artery disease (CAD) and myocardial infarction (MI) in a population of subjects with angiographic documentation of their coronary vessels. In brief, the CAD group had angiographically documented severe coronary atherosclerosis, the majority of them being candidates for coronary artery bypass grafting or percutaneous coronary intervention. Control subjects were selected such that they had normal coronary arteries, being submitted to coronary angiography for reasons other than CAD. Controls with history or clinical evidence of atherosclerosis in vascular districts beyond the coronary bed were excluded. Information on MI diagnoses was gathered through medical records showing diagnostic electrocardiogram and enzyme changes, and/or the typical sequelae of MI on ventricular angiography. The study was approved by local Ethical Committee. Informed consent was obtained from all the patients after a full explanation of the study.

Cohort from Johns Hopkins: The study group from Baltimore is comprised of The Johns Hopkins University Sibling and Family Heart Study, G-Cal, and GeneSTAR studies. The subjects consisted of families identified from 1983-2006 from probands with premature coronary disease event (before 60 years of age). Probands with documented CAD were identified at the time of hospitalization in any of the Baltimore area hospitals. Their apparently healthy siblings without CAD were recruited as well as adult offspring and spouses. Of probands, generally 24% had an MI as their index event, 65% had a PCI and/or CABG, 8.4% had angina with angiography documented CAD and were treated medically, 1.7% had sudden cardiac death, and 1.7% had angiographic documented coronary stenosis with an abnormal stress test and no symptoms.

Cohort from WTCCC: This study cohort has been described previously (Nature 447:661-78 (2007)). Summary statistics from a genome-wide association study performed on these samples is publicly available at http://www.wtccc.org.uk/info/summary_stats.shtml.

Reanalysis of the markers presented in Table 1 was performed using the expanded dataset of 3,047 individuals diagnosed with coronary artery disease, 2,395 diagnosed with myocardial infarction, and 28,321 population controls. The results are presented in Table 3.

The top 100 markers in the scan were explored further by replication analysis in six cohorts from Durham (N.C., US), Philadelphia (Pa., US), Atlanta (Ga., US), John Hopkins University (Maryland, US), Italy, and in a dataset from the Wellcom Trust Case Control Consortium (WTCCC; England). The replication cohorts combined comprise 6,108 cases and 19,396 controls. The results of the replication analysis is shown in Table 4A-4H, both separately for each cohort and a combined analysis for all the replication cohorts, as well as a combined for all the cohorts, including the Icelandic discovery cohort. Many of the variants discovered in the Icelandic discovery cohort show overall significant association in the combined replication groups. The effects are modest, which explains why some cohorts do not indicate significant association, while other cohorts do so.

In the combined analysis of all the groups (9,155 cases; 47,717 controls; Table 4H), marker rs11751605 stands out as the most significant, with a combined P-value of 1.16×10⁻⁸. This is a highly significant number, and in fact represents statistical significance at the genome-wide level, after applying the conservative Bonferroni correction for the number of statistical tests performed (approx. 300,000 in the combined analysis). It should be noted that the number of tests performed in the replication effort is much smaller; consequently, the correction to be applied to correct for the number of tests is smaller, or 100 (giving P-values of 0.05/100, or about 0.0005 as significant after correction). Several markers meet this threshold of significance.

TABLE 3 Association results for SNPs showing association to myoardial infarction (MI) and coronary artery disease (CAD). The results are based on a genomic scan using 2,395 MI samples, 3,047 CAD samples, and 28,321 controls. The columns indicate (1) chromosome, (2) position in NCBI Build 36, (3) the associating allele (4), rs name of the SNP, (5) frequency of the associating allele in controls, (6) the number of controls, (7), the p-value for association to MI, (8) the Relative Risk of association to MI, (9) the frequency of the associating allele in MI patients, (10) the number of MI patients, (11) the p-value of association to CAD, (12) the Relative Risk of association to CAD, (13) the frequency of the associating allele in CAD patients, (14) the number of CAD patients. Pos in RR f N Chr SNP Build 36 Allele f (con) N (con) P (MI) RR (MI) f (MI) N (MI) P (CAD) (CAD) (CAD) (CAD) C01 rs10462018 7802214 C 0.821 28185 1.40E−02 1.11 0.836 2390 1.20E−01 1.06 0.830 3040 C01 rs2946534 18647370 T 0.571 28302 3.40E−04 1.13 0.599 2394 4.50E−04 1.11 0.596 3046 C01 rs3748744 19828833 G 0.898 28280 6.30E−02 1.11 0.907 2394 3.30E−02 1.11 0.908 3046 C01 rs7523192 19835634 T 0.813 28296 7.10E−02 1.08 0.824 2395 1.50E−01 1.06 0.821 3047 C01 rs7535952 19846151 A 0.722 28166 6.60E−02 1.07 0.735 2355 6.40E−02 1.06 0.734 3003 C01 rs2072671 20788288 C 0.313 28310 0.0011 1.12 0.338 2395 1.30E−03 1.11 0.335 3047 C01 rs12724604 20948045 A 0.037 28248 9.80E−03 1.23 0.045 2386 2.10E−02 1.19 0.043 3037 C01 rs12741305 21192774 C 0.038 28320 0.0087 1.23 0.046 2393 2.30E−02 1.18 0.044 3044 C01 rs10799128 29476586 T 0.200 28211 0.062 1.08 0.212 2378 1.40E−01 1.06 0.208 3029 C01 rs1932397 29835784 G 0.822 28320 1.80E−03 1.15 0.841 2395 2.80E−03 1.13 0.839 3047 C01 rs407838 30585414 C 0.846 28311 0.0039 1.14 0.863 2395 4.70E−03 1.13 0.861 3047 C01 rs593993 30648371 C 0.838 28311 0.00099 1.16 0.858 2392 9.30E−04 1.15 0.856 3044 C01 rs12029866 30657936 G 0.775 28318 0.0043 1.12 0.794 2395 4.40E−03 1.11 0.792 3047 C01 rs12126748 31307750 A 0.346 27660 0.0018 1.11 0.371 2341 9.90E−03 1.08 0.365 2979 C01 rs661221 40866417 G 0.805 28299 1.80E−02 1.10 0.820 2392 2.40E−01 1.05 0.811 3044 C01 rs7524868 40879361 G 0.306 28288 1.80E−02 1.09 0.324 2385 1.20E−01 1.05 0.316 3036 C01 rs7520394 40882456 T 0.649 28231 0.0014 1.12 0.674 2390 7.50E−02 1.06 0.662 3041 C01 rs2294512 54142894 G 0.688 28321 0.064 1.07 0.702 2395 7.00E−02 1.06 0.701 3047 C01 rs4927219 55524409 G 0.603 28319 4.50E−03 1.10 0.625 2395 3.80E−03 1.09 0.624 3047 C01 rs2991515 57656898 T 0.483 28319 0.0033 1.10 0.507 2395 7.70E−04 1.10 0.508 3047 C01 rs11208061 63165253 A 0.346 27897 0.0014 1.12 0.371 2375 6.10E−03 1.09 0.365 3012 C01 rs12134779 63168930 T 0.292 28320 0.0000094 1.17 0.325 2394 2.80E−04 1.12 0.316 3046 C01 rs6696619 63225377 C 0.673 28302 6.70E−02 1.07 0.687 2395 3.20E−01 1.03 0.680 3047 C01 rs1747924 64311549 T 0.810 28282 0.019 1.10 0.825 2395 0.23 1.05 0.817 3044 C01 rs2806535 64350358 A 0.483 28297 0.013 1.09 0.504 2394 0.0066 1.08 0.503 3043 C01 rs3818513 65646625 C 0.462 28320 0.049 1.07 0.477 2395 0.38 1.03 0.468 3047 C01 rs2025805 65722466 C 0.567 28315 0.023 1.08 0.585 2395 0.015 1.08 0.584 3047 C01 rs10489554 69921136 T 0.776 28311 0.0089 1.11 0.793 2395 0.038 1.08 0.788 3046 C01 rs10518531 76871826 C 0.845 28121 0.032 1.10 0.858 2359 0.06 1.08 0.855 3004 C01 rs1566250 76986952 G 0.703 28309 0.00084 1.13 0.728 2395 0.0011 1.11 0.725 3047 C01 rs1412414 78711365 G 0.620 28290 2.40E−03 1.11 0.644 2394 0.00059 1.11 0.645 3044 C01 rs1543675 78719467 C 0.380 28318 0.0013 1.11 0.405 2395 0.0036 1.09 0.401 3046 C01 rs1030414 81241030 G 0.902 28318 0.039 1.12 0.912 2395 0.046 1.11 0.911 3046 C01 rs7531507 81261795 G 0.922 28296 0.039 1.14 0.930 2394 0.021 1.14 0.931 3045 C01 rs12032817 82949953 G 0.375 28320 4.30E−03 1.10 0.398 2395 0.0046 1.09 0.396 3047 C01 rs1360903 86345051 G 0.508 28234 0.0055 1.09 0.531 2389 0.006 1.09 0.529 3040 C01 rs10801705 89272970 A 0.462 28318 0.0074 1.09 0.483 2394 0.018 1.07 0.479 3046 C01 rs4147861 94244536 G 0.922 28179 0.0019 1.22 0.935 2359 0.0012 1.21 0.934 3009 C01 rs10494048 106996582 T 0.381 28261 0.00089 1.12 0.407 2394 0.014 1.08 0.399 3044 C01 rs2335793 107945406 C 0.890 28309 0.006 1.16 0.904 2393 0.014 1.13 0.901 3045 C01 rs6688859 113577284 T 0.683 28320 0.19 1.05 0.693 2395 0.11 1.05 0.694 3047 C01 rs773586 113643259 A 0.488 28315 0.015 1.08 0.508 2395 0.0096 1.08 0.507 3047 C01 rs773588 113646347 C 0.282 28300 0.11 1.06 0.293 2394 0.023 1.08 0.297 3046 C01 rs2797409 114131725 C 0.248 28318 0.0024 1.12 0.269 2395 0.0036 1.10 0.266 3047 C01 rs2476601 114179091 A 0.129 28313 0.000031 1.21 0.152 2395 0.000097 1.18 0.148 3047 C01 rs1217407 114195271 A 0.247 28266 2.10E−03 1.12 0.269 2394 0.0031 1.10 0.266 3045 C01 rs1970568 149842380 T 0.815 28313 0.001 1.15 0.835 2395 0.021 1.09 0.828 3047 C01 rs6702842 149874720 G 0.272 28099 0.0072 1.10 0.292 2379 0.072 1.06 0.284 3029 C01 rs2495392 149943873 G 0.278 28312 0.0038 1.11 0.299 2395 0.052 1.07 0.291 3046 C01 rs12066445 150007044 A 0.302 28320 5.90E−04 1.13 0.327 2395 0.0094 1.09 0.319 3047 C01 rs9826 150045523 G 0.329 28106 0.0021 1.11 0.353 2377 0.03 1.07 0.344 3022 C01 rs949969 150059438 T 0.199 28317 0.016 1.10 0.214 2395 0.039 1.08 0.211 3047 C01 rs4845552 151746622 G 0.128 28269 0.0025 1.15 0.145 2393 0.00041 1.16 0.146 3044 C01 rs822519 154107330 A 0.935 28320 0.024 1.17 0.944 2395 0.025 1.15 0.943 3047 C01 rs12567958 154861280 C 0.265 28272 0.024 1.09 0.282 2392 0.075 1.06 0.277 3043 C01 rs4971177 156256292 T 0.914 28315 5.20E−04 1.24 0.929 2395 0.0015 1.19 0.927 3047 C01 rs2651860 163647679 T 0.785 28321 0.011 1.11 0.801 2395 0.012 1.10 0.800 3046 C01 rs11582943 169209225 A 0.941 28257 0.0019 1.26 0.953 2388 0.00098 1.25 0.952 3039 C01 rs12033847 174294601 T 0.460 27452 0.011 1.09 0.481 2360 0.0029 1.09 0.482 2999 C01 rs2175177 174450679 A 0.461 28011 6.20E−03 1.09 0.483 2386 0.0016 1.10 0.484 3030 C01 rs4651384 185685027 G 0.687 28319 0.0025 1.11 0.709 2395 0.028 1.07 0.702 3047 C01 rs2250227 185696690 C 0.337 28310 0.0058 1.10 0.358 2395 0.021 1.07 0.353 3047 C01 rs1339083 185819288 A 0.345 28315 0.01 1.09 0.365 2395 0.0018 1.10 0.367 3047 C01 rs2383658 185847926 G 0.394 28312 0.022 1.08 0.412 2395 0.0057 1.09 0.414 3047 C01 rs792446 210623301 G 0.617 28317 0.016 1.09 0.636 2395 0.052 1.06 0.631 3046 C01 rs11118175 217155936 G 0.077 28315 0.026 1.14 0.087 2395 0.0077 1.15 0.087 3047 C01 rs2642438 219036651 G 0.712 11355 0.0079 1.12 0.735 1767 0.083 1.07 0.726 2084 C01 rs1519463 219944762 G 0.508 28316 0.0096 1.09 0.529 2395 0.0035 1.09 0.530 3047 C01 rs1341449 239642925 A 0.548 28236 0.0079 1.09 0.570 2373 0.0083 1.08 0.568 3024 C01 rs3014559 239649291 A 0.550 28231 0.022 1.08 0.569 2393 0.015 1.08 0.568 3044 C01 rs12068067 245092561 G 0.774 28183 0.0059 1.12 0.793 2390 0.0064 1.10 0.791 3041 C02 rs7608117 11183423 T 0.487 28310 0.0037 1.10 0.511 2393 0.028 1.07 0.503 3044 C02 rs10929777 12079564 C 0.305 28316 1.60E−01 1.05 0.315 2395 0.22 1.04 0.313 3047 C02 rs11897395 16671068 C 0.890 28200 0.0085 1.15 0.903 2379 0.028 1.11 0.900 3028 C02 rs2342551 17178028 T 0.713 28317 0.0023 1.12 0.735 2395 0.012 1.09 0.729 3047 C02 rs12467812 19858951 G 0.330 28257 0.035 1.08 0.346 2395 0.018 1.08 0.346 3047 C02 rs10200481 24191365 A 0.110 28314 0.018 1.13 0.122 2395 0.079 1.09 0.118 3047 C02 rs6747236 35901725 T 0.717 28311 0.0021 1.12 0.739 2395 0.0098 1.09 0.734 3047 C02 rs10203034 35916379 A 0.681 28318 0.0032 1.11 0.703 2395 0.018 1.08 0.697 3047 C02 rs963731 39070377 C 0.954 27813 0.0019 1.30 0.964 2347 0.001 1.28 0.963 2991 C02 rs2168043 39185597 C 0.867 28278 0.0077 1.14 0.881 2395 0.0042 1.14 0.881 3047 C02 rs10202624 42368892 A 0.095 28319 0.028 1.13 0.106 2395 0.04 1.11 0.104 3047 C02 rs6724757 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28249 0.28 1.04 0.588 2392 0.18 1.04 0.589 3042 C02 rs6547152 77634997 C 0.790 28305 0.12 1.07 0.801 2393 0.1 1.06 0.800 3044 C02 rs2861264 78220585 T 0.107 28303 0.0057 1.15 0.121 2394 0.024 1.11 0.117 3046 C02 rs11675205 85323792 A 0.255 28302 0.0005 1.14 0.280 2394 0.0011 1.11 0.276 3046 C02 rs2245113 118108945 A 0.179 28279 0.017 1.10 0.194 2392 0.08 1.07 0.189 3043 C02 rs1477451 118164844 T 0.126 28320 0.0012 1.17 0.144 2395 0.0099 1.12 0.139 3047 C02 rs1395930 123468570 T 0.499 28303 3.20E−03 1.10 0.523 2393 0.00012 1.12 0.528 3045 C02 rs2661006 123482987 T 0.497 28301 0.0035 1.10 0.521 2391 0.00013 1.12 0.525 3042 C02 rs3943703 127613790 C 0.214 28280 0.02 1.09 0.229 2395 0.06 1.07 0.225 3046 C02 rs4662743 128067278 T 0.515 28231 0.042 1.07 0.531 2392 0.016 1.07 0.533 3042 C02 rs2244871 128115310 C 0.413 28251 0.013 1.09 0.433 2394 0.015 1.08 0.430 3046 C02 rs2321299 134350130 C 0.571 28315 0.034 1.07 0.588 2395 0.21 1.04 0.580 3046 C02 rs2139311 134628584 C 0.601 28304 0.0044 1.10 0.624 2394 0.0022 1.10 0.623 3045 C02 rs12473666 134639501 T 0.140 28308 0.03 1.10 0.153 2394 0.11 1.07 0.149 3046 C02 rs10496721 134648929 T 0.175 28306 0.094 1.07 0.185 2394 0.39 1.03 0.179 3046 C02 rs1257208 134700540 A 0.140 28317 0.017 1.12 0.154 2395 0.0067 1.12 0.154 3047 C02 rs2268365 169802415 G 0.127 28319 0.038 1.10 0.138 2393 0.045 1.09 0.136 3045 C02 rs1837241 171017898 A 0.696 28315 0.00086 1.13 0.720 2395 0.0024 1.10 0.716 3047 C02 rs1399959 172140552 G 0.668 28291 0.0069 1.10 0.688 2393 0.026 1.07 0.683 3044 C02 rs951917 172220171 T 0.383 28319 0.015 1.08 0.403 2395 0.3 1.03 0.391 3047 C02 rs4668412 172328016 A 0.709 28319 0.0031 1.11 0.730 2395 0.018 1.08 0.724 3047 C02 rs6758704 172363343 T 0.709 28303 3.10E−03 1.11 0.730 2395 0.02 1.08 0.724 3047 C02 rs10165126 172528561 C 0.702 28297 0.00068 1.13 0.727 2394 0.003 1.10 0.721 3046 C02 rs6718013 172577431 G 0.536 28318 0.0027 1.10 0.560 2395 0.073 1.05 0.549 3047 C02 rs921083 176453128 G 0.781 28310 0.0092 1.11 0.798 2394 0.04 1.08 0.794 3044 C02 rs12621733 176499888 G 0.901 28320 0.05 1.12 0.911 2395 0.056 1.10 0.910 3047 C02 rs1946815 183006405 G 0.219 28310 0.019 1.09 0.235 2395 0.061 1.07 0.231 3047 C02 rs4666836 183055419 T 0.223 28298 0.075 1.07 0.236 2394 0.15 1.05 0.232 3046 C02 rs6434921 197828442 A 0.397 28313 0.01 1.09 0.418 2395 0.03 1.07 0.413 3045 C02 rs6704822 203370024 G 0.915 28086 0.021 1.15 0.926 2380 0.13 1.09 0.922 3030 C02 rs6435401 208537772 A 0.339 28305 0.015 1.09 0.358 2394 0.025 1.07 0.355 3044 C02 rs9288396 209243202 T 0.205 28308 0.0077 1.11 0.223 2395 0.0013 1.12 0.225 3047 C02 rs4442936 211847782 G 0.280 28075 0.00038 1.14 0.307 2367 0.00015 1.13 0.306 3016 C02 rs12329252 212093968 T 0.681 28321 0.0047 1.11 0.703 2395 0.0059 1.09 0.700 3047 C02 rs17406681 212111632 T 0.277 28319 0.0075 1.10 0.297 2394 0.022 1.08 0.292 3046 C02 rs10932529 214852965 A 0.250 28318 2.80E−02 1.09 0.266 2395 0.027 1.08 0.264 3047 C02 rs2216544 214891122 A 0.257 28310 0.031 1.08 0.273 2395 0.027 1.08 0.272 3047 C02 rs13417729 215894070 C 0.715 11415 0.0067 1.13 0.739 1775 0.011 1.11 0.736 2094 C02 rs1478581 218000897 G 0.821 28316 0.0043 1.13 0.839 2395 0.0014 1.13 0.839 3045 C02 rs9288639 229462042 C 0.080 28295 0.021 1.14 0.091 2392 0.059 1.11 0.088 3042 C02 rs12617590 234708220 C 0.201 28301 0.0073 1.11 0.219 2395 0.015 1.09 0.215 3047 C02 rs12052982 241760005 A 0.956 28309 0.00035 1.36 0.967 2393 0.00018 1.34 0.967 3045 C03 rs17565216 2631107 C 0.366 28306 0.0031 1.10 0.390 2392 0.0033 1.09 0.387 3044 C03 rs341973 5243162 A 0.508 28284 0.021 1.08 0.527 2393 0.051 1.06 0.523 3044 C03 rs7638636 6735499 A 0.511 27822 0.031 1.07 0.529 2376 0.11 1.05 0.523 3013 C03 rs978658 6741178 G 0.615 28313 0.13 1.05 0.627 2394 0.26 1.04 0.623 3046 C03 rs12491369 6764265 G 0.577 28320 0.31 1.03 0.585 2395 0.63 1.01 0.581 3047 C03 rs779710 7486375 A 0.596 28311 0.088 1.06 0.610 2395 0.15 1.04 0.607 3047 C03 rs752299 7494813 T 0.685 11413 1.50E−03 1.15 0.714 1775 0.0056 1.12 0.708 2094 C03 rs2128163 14269176 G 0.539 28300 0.046 1.07 0.556 2395 0.025 1.07 0.556 3047 C03 rs6772823 14276852 G 0.280 27955 0.0033 1.11 0.302 2370 0.00061 1.12 0.303 3014 C03 rs1870480 22619924 G 0.388 28314 0.14 1.05 0.400 2395 0.089 1.05 0.400 3047 C03 rs6763490 25122716 C 0.600 28310 0.00071 1.12 0.627 2395 0.007 1.09 0.619 3047 C03 rs13079598 29295837 A 0.906 28315 0.0015 1.20 0.920 2395 0.0022 1.17 0.918 3046 C03 rs2853705 39306976 T 0.209 28313 0.0043 1.12 0.228 2395 0.0065 1.10 0.226 3047 C03 rs1530733 54364155 A 0.155 28318 0.029 1.10 0.168 2395 0.033 1.09 0.167 3047 C03 rs603052 61765300 T 0.778 28301 0.0083 1.11 0.796 2394 0.041 1.08 0.791 3046 C03 rs1997366 62414626 C 0.798 28304 1.80E−01 1.06 0.807 2394 0.21 1.05 0.805 3045 C03 rs1534725 62420416 T 0.788 28304 4.80E−02 1.08 0.801 2394 0.041 1.08 0.800 3046 C03 rs9874646 62437858 T 0.717 28314 0.11 1.06 0.729 2394 0.16 1.05 0.726 3046 C03 rs1452075 62456103 T 0.739 28228 0.2 1.05 0.748 2386 0.15 1.05 0.748 3033 C03 rs7653410 63619805 C 0.324 28036 0.01 1.09 0.344 2383 0.051 1.06 0.338 3030 C03 rs1563545 66782776 G 0.530 28035 1.50E−02 1.08 0.550 2369 0.015 1.07 0.548 3016 C03 rs2046867 72863765 T 0.279 28307 0.0088 1.10 0.298 2395 0.021 1.08 0.294 3047 C03 rs7632726 72895436 T 0.310 28319 0.013 1.09 0.329 2395 0.026 1.07 0.325 3047 C03 rs2208 72954463 A 0.268 28315 0.0087 1.10 0.287 2395 0.024 1.08 0.283 3047 C03 rs4234186 74348999 A 0.945 28271 0.0037 1.25 0.956 2390 0.13 1.11 0.950 3040 C03 rs2055707 78706269 A 0.418 28182 0.00039 1.12 0.447 2392 0.0016 1.10 0.441 3044 C03 rs13075335 83006051 T 0.904 28256 1.60E−02 1.15 0.915 2393 0.047 1.11 0.913 3044 C03 rs1531377 99825932 T 0.177 28216 0.013 1.11 0.192 2391 0.2 1.05 0.184 3041 C03 rs3796139 99861391 G 0.150 28071 0.012 1.12 0.165 2375 0.2 1.05 0.157 3018 C03 rs9847700 124635632 G 0.851 28188 0.00017 1.20 0.872 2345 0.00021 1.17 0.870 2995 C03 rs6438839 125536191 A 0.078 28316 0.0077 1.17 0.090 2395 0.0044 1.16 0.090 3047 C03 rs10935515 146038973 C 0.576 26370 0.00024 1.13 0.606 2294 0.00051 1.11 0.602 2902 C03 rs4401402 146073240 T 0.584 28314 3.20E−03 1.10 0.608 2394 0.0032 1.09 0.606 3046 C03 rs13061557 146128702 T 0.698 28295 0.092 1.06 0.710 2395 0.13 1.05 0.708 3047 C03 rs10935523 146138781 A 0.740 28317 0.036 1.08 0.754 2395 0.026 1.08 0.754 3047 C03 rs1430435 170561887 G 0.501 28314 0.017 1.08 0.521 2395 0.056 1.06 0.515 3047 C03 rs756644 170567521 A 0.429 28313 2.20E−03 1.11 0.454 2394 0.023 1.07 0.446 3046 C03 rs1549100 175400363 T 0.732 28237 0.078 1.07 0.745 2386 0.28 1.04 0.739 3038 C03 rs1421420 175408319 A 0.727 28307 0.037 1.08 0.742 2395 0.15 1.05 0.737 3047 C03 rs2111956 175432500 G 0.763 28317 0.043 1.08 0.777 2395 0.099 1.06 0.773 3046 C03 rs6803944 186606110 C 0.845 28320 0.0084 1.13 0.860 2395 0.012 1.11 0.858 3047 C03 rs9864293 191695400 C 0.387 28308 0.00012 1.14 0.418 2395 0.00013 1.12 0.415 3046 C03 rs883279 194931805 C 0.907 28311 0.061 1.11 0.916 2394 0.03 1.12 0.916 3046 C03 rs4497978 195990481 A 0.666 28228 0.00031 1.14 0.694 2375 0.0019 1.10 0.688 3023 C04 rs6822427 3749870 A 0.488 28256 0.022 1.08 0.506 2391 0.016 1.07 0.506 3040 C04 rs3756193 8284241 G 0.461 28262 0.0072 1.09 0.483 2393 0.004 1.09 0.482 3043 C04 rs714086 9922140 G 0.761 28317 0.013 1.10 0.778 2395 0.11 1.06 0.771 3047 C04 rs4697653 10337857 G 0.524 28161 0.0021 1.11 0.549 2392 0.0081 1.08 0.543 3040 C04 rs2170752 10493178 T 0.576 28317 0.011 1.09 0.597 2395 0.077 1.05 0.589 3047 C04 rs959233 10511257 G 0.446 28291 2.60E−02 1.08 0.464 2394 0.02 1.07 0.463 3044 C04 rs10011464 10515465 T 0.462 28191 0.031 1.07 0.480 2375 0.038 1.06 0.478 3025 C04 rs7442366 16944686 T 0.824 28321 0.024 1.10 0.838 2395 0.066 1.08 0.835 3047 C04 rs2697684 17045056 G 0.774 28318 0.033 1.09 0.788 2395 0.018 1.09 0.788 3047 C04 rs1827591 21341284 G 0.538 28319 0.0079 1.09 0.560 2395 0.012 1.08 0.557 3047 C04 rs6448072 21352329 C 0.659 28318 0.017 1.09 0.677 2395 0.009 1.09 0.677 3047 C04 rs10516402 21407661 C 0.505 28313 0.0023 1.10 0.530 2394 0.0024 1.09 0.527 3046 C04 rs4282162 21426819 T 0.530 28305 0.002 1.11 0.555 2395 0.0031 1.09 0.552 3047 C04 rs4377576 21434824 C 0.541 28316 0.0034 1.10 0.565 2395 0.0044 1.09 0.562 3047 C04 rs2060515 29994854 T 0.114 28189 0.059 1.10 0.124 2379 0.064 1.09 0.123 3028 C04 rs4132132 30610399 G 0.451 28229 0.12 1.05 0.464 2390 0.17 1.04 0.461 3040 C04 rs10517277 33143198 C 0.102 28290 0.0086 1.15 0.115 2394 0.041 1.10 0.111 3046 C04 rs3849018 37325240 T 0.280 28319 0.003 1.11 0.301 2395 0.0016 1.11 0.301 3046 C04 rs4447895 40092010 C 0.887 28318 0.015 1.14 0.899 2395 0.0087 1.13 0.899 3047 C04 rs6447404 44714926 G 0.620 11414 0.015 1.10 0.643 1775 0.048 1.08 0.638 2094 C04 rs7661204 45728007 T 0.449 28320 0.0055 0.91 0.427 2395 0.00074 0.91 0.425 3047 C04 rs10026644 82020315 G 0.924 27964 0.0003 1.27 0.939 2382 0.01 1.16 0.933 3028 C04 rs10026120 82037699 T 0.959 28199 0.006 1.28 0.968 2393 0.03 1.19 0.965 3040 C04 rs6830629 82083395 A 0.975 28273 0.0036 1.39 0.982 2393 0.034 1.24 0.979 3043 C04 rs2589506 87158716 G 0.456 28313 0.018 1.08 0.475 2395 0.0053 1.09 0.476 3047 C04 rs2199309 87318595 C 0.219 26388 0.022 1.10 0.235 2276 0.0032 1.11 0.238 2883 C04 rs10516770 87391122 T 0.056 28310 0.083 1.13 0.062 2395 0.014 1.16 0.064 3047 C04 rs2924936 89860537 G 0.871 28318 0.11 1.08 0.879 2395 0.019 1.11 0.882 3047 C04 rs13130 89867868 T 0.872 28227 0.11 1.08 0.880 2388 0.019 1.11 0.883 3039 C04 rs6850673 96366883 C 0.142 28314 0.014 1.12 0.156 2394 0.0082 1.12 0.156 3046 C04 rs10516987 97050762 G 0.798 28265 0.0073 1.12 0.815 2385 0.019 1.09 0.812 3035 C04 rs1982346 106798203 C 0.058 27647 0.00038 1.26 0.072 2352 0.0016 1.21 0.069 2991 C04 rs6820367 119312058 A 0.353 28319 0.036 1.07 0.369 2395 0.078 1.06 0.365 3047 C04 rs6534683 129601758 T 0.656 28310 0.076 1.06 0.670 2395 0.034 1.07 0.671 3047 C04 rs7690289 129628963 T 0.637 27978 0.028 1.08 0.654 2381 0.0076 1.09 0.655 3023 C04 rs4549394 129650748 T 0.102 28313 0.094 1.09 0.110 2395 0.14 1.07 0.108 3047 C04 rs4383635 131414021 A 0.491 28225 0.031 1.07 0.508 2394 0.0099 1.08 0.510 3045 C04 rs1027884 131431891 T 0.497 28311 0.02 1.08 0.516 2395 0.0072 1.08 0.517 3047 C04 rs4864193 134641403 C 0.961 28307 0.16 1.13 0.965 2395 0.15 1.12 0.965 3047 C04 rs10028163 138689635 G 0.207 28316 0.0012 1.14 0.228 2395 0.00075 1.13 0.227 3047 C04 rs7669668 139472904 T 0.123 28319 0.02 1.12 0.136 2395 0.16 1.06 0.130 3047 C04 rs723794 147095001 T 0.773 28318 0.011 1.11 0.791 2395 0.037 1.08 0.786 3047 C04 rs2241521 147218561 A 0.239 28318 0.03 1.09 0.254 2395 0.017 1.09 0.255 3047 C04 rs17326199 161219141 G 0.214 28307 0.0099 1.11 0.231 2393 0.0041 1.11 0.231 3045 C04 rs17359034 161797877 T 0.390 28227 0.011 1.09 0.410 2394 0.044 1.06 0.404 3046 C04 rs12503470 162109433 T 0.383 28267 0.049 1.07 0.399 2394 0.019 1.07 0.400 3046 C04 rs9942159 162382460 T 0.380 28203 0.005 1.10 0.402 2383 0.0029 1.09 0.401 3034 C04 rs958247 162412247 A 0.289 28271 0.0036 1.11 0.310 2393 0.0014 1.11 0.310 3043 C04 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1.08 0.580 3038 C07 rs2192658 78023891 T 0.078 28313 0.032 1.13 0.088 2394 0.02 1.13 0.087 3045 C07 rs6467882 81513097 C 0.168 28308 0.024 1.10 0.182 2395 0.03 1.09 0.180 3045 C07 rs2373018 85426196 G 0.371 28312 0.015 1.09 0.391 2395 0.0087 1.08 0.390 3045 C07 rs10276025 85428427 T 0.371 28319 0.014 1.09 0.391 2395 0.0084 1.08 0.390 3047 C07 rs1012995 85495735 C 0.218 28145 0.029 1.09 0.233 2375 0.024 1.08 0.232 3022 C07 rs2373593 86874878 A 0.864 28311 0.0018 1.17 0.881 2395 0.0026 1.14 0.879 3047 C07 rs31662 86883520 G 0.864 28315 0.0018 1.17 0.881 2395 0.0021 1.15 0.879 3047 C07 rs999885 99539112 T 0.505 27962 0.02 1.08 0.524 2351 0.033 1.07 0.521 2997 C07 rs7804867 102820993 A 0.208 28315 0.056 1.08 0.221 2395 0.16 1.05 0.216 3046 C07 rs2270019 102844244 G 0.168 28300 0.0047 1.13 0.186 2392 0.012 1.10 0.182 3044 C07 rs17152161 102928939 C 0.158 28304 0.002 1.14 0.177 2395 0.00069 1.14 0.177 3047 C07 rs10282605 102949606 C 0.188 28303 0.00052 1.15 0.210 2395 0.00081 1.13 0.208 3047 C07 rs1029396 116812056 G 0.071 28315 0.0018 1.21 0.084 2395 0.000061 1.24 0.086 3047 C07 rs2283054 116913637 A 0.070 28319 0.0022 1.20 0.083 2394 0.000086 1.24 0.086 3046 C07 rs2237721 116920956 C 0.070 28314 0.0022 1.20 0.083 2395 0.000088 1.24 0.085 3047 C07 rs10487368 116927331 T 0.194 28319 0.034 1.09 0.208 2395 0.0033 1.11 0.212 3047 C07 rs2237723 116934783 T 0.197 28304 0.032 1.09 0.211 2395 0.0031 1.11 0.215 3047 C07 rs2237724 116941395 A 0.194 28320 0.034 1.09 0.208 2395 0.0033 1.11 0.212 3047 C07 rs2027945 116975058 A 0.194 28316 0.032 1.09 0.208 2395 0.0031 1.11 0.212 3047 C07 rs213977 117025681 G 0.412 28316 0.002 1.11 0.437 2395 0.00051 1.11 0.438 3047 C07 rs2299445 117033551 C 0.080 28315 0.00061 1.21 0.096 2394 0.000033 1.24 0.098 3046 C07 rs213987 117048529 T 0.328 28300 0.0036 1.11 0.351 2395 0.0017 1.10 0.350 3046 C07 rs12534186 117079572 T 0.081 28310 0.00056 1.22 0.096 2394 0.00003 1.24 0.098 3046 C07 rs975722 117120150 G 0.392 28318 0.0044 1.10 0.414 2395 0.0009 1.11 0.415 3047 C07 rs324594 136305863 C 0.266 28310 0.0023 1.12 0.289 2395 0.0018 1.11 0.287 3047 C07 rs11761344 136433359 T 0.119 28295 0.0042 1.15 0.134 2393 0.0046 1.13 0.132 3045 C07 rs7791708 144537777 A 0.677 28231 0.0046 1.11 0.698 2387 0.013 1.08 0.694 3035 C07 rs10271435 147385206 A 0.063 28313 0.05 1.14 0.071 2395 0.0065 1.17 0.073 3047 C07 rs10277774 150219733 C 0.390 28309 0.11 1.06 0.402 2394 0.11 1.05 0.401 3046 C07 rs11762978 150241033 A 0.654 28261 0.0057 1.10 0.676 2391 0.0029 1.10 0.675 3043 C07 rs2373885 150309013 A 0.749 28303 0.014 1.10 0.766 2395 0.013 1.09 0.765 3046 C07 rs11769878 157343230 C 0.741 27759 0.0011 1.13 0.764 2355 0.0054 1.10 0.759 2996 C08 rs722782 506479 C 0.892 28261 0.011 1.15 0.904 2363 0.026 1.12 0.902 3014 C08 rs7386449 1315247 A 0.681 28312 0.0066 1.10 0.701 2395 0.0044 1.10 0.700 3046 C08 rs10503316 5498753 C 0.776 28318 0.022 1.10 0.792 2395 0.058 1.07 0.788 3047 C08 rs6991017 5508780 T 0.793 28273 0.013 1.11 0.809 2393 0.044 1.08 0.805 3044 C08 rs890014 5835084 C 0.762 28320 0.15 1.06 0.772 2395 0.25 1.04 0.769 3047 C08 rs7006687 18277862 T 0.579 28306 0.0018 1.11 0.604 2392 0.00068 1.11 0.604 3044 C08 rs334198 18933089 C 0.922 28309 0.037 0.89 0.913 2393 0.082 0.91 0.915 3045 C08 rs11775256 23107430 T 0.274 28317 0.048 1.07 0.288 2395 0.029 1.07 0.288 3047 C08 rs4732849 28249765 T 0.275 28321 0.0069 1.10 0.295 2395 0.13 1.05 0.285 3047 C08 rs904053 28258855 G 0.224 28313 0.035 1.08 0.238 2395 0.43 1.03 0.229 3047 C08 rs12547858 32606595 T 0.193 28139 0.0023 1.13 0.213 2382 0.0065 1.11 0.209 3025 C08 rs10503927 32662772 T 0.476 28318 0.0011 1.11 0.503 2395 0.00025 1.11 0.503 3047 C08 rs9656744 32836025 T 0.509 28311 0.0033 1.10 0.533 2394 0.01 1.08 0.528 3044 C08 rs16880128 32852935 G 0.441 27756 0.0014 1.11 0.467 2362 0.014 1.08 0.459 3002 C08 rs7017907 37527288 C 0.088 28266 0.15 1.08 0.095 2385 0.86 1.01 0.089 3037 C08 rs7830101 39527585 T 0.278 28099 0.071 1.07 0.291 2372 0.027 1.08 0.292 3021 C08 rs7819949 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28218 0.0015 1.23 0.939 2380 0.0088 1.17 0.936 3028 C08 rs3102526 96858538 G 0.647 27995 0.013 1.09 0.666 2382 0.015 1.08 0.664 3019 C08 rs3134517 96859237 G 0.647 28308 0.016 1.09 0.666 2395 0.018 1.08 0.664 3047 C08 rs2440213 97275495 A 0.360 28316 0.0016 1.11 0.385 2395 0.0078 1.09 0.379 3047 C08 rs1992087 97552943 G 0.261 28309 0.019 1.09 0.278 2394 0.028 1.08 0.276 3046 C08 rs1075479 97849402 A 0.792 28280 0.017 1.10 0.808 2390 0.075 1.07 0.803 3039 C08 rs4620270 125506992 T 0.133 28307 0.082 1.09 0.143 2394 0.041 1.09 0.143 3046 C08 rs2648896 129169615 C 0.149 28304 0.0004 1.17 0.170 2395 0.00052 1.15 0.167 3047 C08 rs2302793 129177879 G 0.434 28273 0.0018 1.11 0.459 2382 0.0075 1.08 0.454 3033 C08 rs3931282 129179963 T 0.568 28319 0.0016 0.90 0.543 2395 0.007 0.92 0.548 3047 C08 rs10505507 129311983 A 0.923 28320 0.000057 1.30 0.939 2395 0.0019 1.20 0.935 3047 C08 rs4451334 138344030 A 0.064 28282 0.1 1.11 0.071 2390 0.13 1.09 0.070 3042 C08 rs4909759 139293683 T 0.263 28309 0.051 1.07 0.277 2395 0.013 1.09 0.279 3047 C08 rs4909761 139294744 T 0.264 28318 0.037 1.08 0.279 2395 0.0088 1.09 0.281 3047 C08 rs747551 143209084 T 0.433 28310 0.0092 1.09 0.454 2393 0.034 1.07 0.449 3045 C08 rs7834060 143220109 G 0.431 28316 0.015 1.08 0.450 2395 0.046 1.06 0.445 3047 C08 rs3934930 143226261 T 0.430 28320 0.014 1.08 0.450 2395 0.043 1.06 0.445 3047 C08 rs11167132 143245585 T 0.216 28136 0.0076 1.11 0.234 2383 0.031 1.08 0.230 3028 C08 rs9644545 143276606 T 0.475 28309 0.0002 1.13 0.505 2394 0.0004 1.11 0.501 3046 C08 rs5297 143952659 C 0.091 28314 0.003 1.18 0.105 2394 0.0072 1.14 0.102 3046 C08 rs7844961 143999186 T 0.092 28314 0.00094 1.19 0.108 2395 0.0035 1.15 0.105 3047 C08 rs4977114 144250835 C 0.028 28320 0.014 1.26 0.035 2395 0.039 1.19 0.033 3047 C09 rs2890795 8437732 T 0.579 28315 0.011 1.09 0.599 2395 0.0031 1.09 0.600 3046 C09 rs10119236 8506194 A 0.297 28304 0.042 1.07 0.313 2395 0.017 1.08 0.314 3047 C09 rs10960174 11743695 G 0.614 28312 0.00026 1.13 0.643 2392 0.000093 1.13 0.642 3043 C09 rs1343705 14600866 G 0.475 28306 0.0019 1.11 0.500 2394 0.0021 1.10 0.498 3046 C09 rs4961695 16318137 C 0.801 28297 0.00029 1.16 0.824 2392 0.00012 1.16 0.823 3042 C09 rs1888955 16319537 A 0.740 28315 0.00025 1.15 0.766 2395 0.0003 1.13 0.763 3047 C09 rs9407756 16321304 G 0.674 28318 0.0021 1.11 0.697 2395 0.013 1.08 0.691 3047 C09 rs12683609 16324761 A 0.572 28317 0.00017 1.13 0.602 2394 0.00038 1.11 0.598 3046 C09 rs1329044 23737791 C 0.156 28317 0.0092 1.12 0.172 2395 0.011 1.11 0.170 3047 C09 rs7038525 23762277 T 0.155 28251 0.0084 1.12 0.171 2393 0.0082 1.11 0.169 3045 C09 rs1452335 28113402 G 0.720 28196 0.018 1.09 0.737 2385 0.022 1.08 0.735 3036 C09 rs1452336 28114180 A 0.500 28241 0.013 1.09 0.520 2389 0.0021 1.10 0.523 3040 C09 rs1452337 28116482 G 0.800 28150 0.047 1.09 0.813 2377 0.078 1.07 0.810 3026 C09 rs2044961 28154645 G 0.573 28307 0.008 1.09 0.594 2395 0.00083 1.11 0.597 3046 C09 rs10758186 33091838 G 0.385 28316 0.052 1.07 0.400 2395 0.096 1.05 0.397 3047 C09 rs943535 72064166 A 0.920 28254 0.01 1.18 0.931 2385 0.0061 1.17 0.931 3034 C09 rs10867740 83153344 C 0.237 28282 0.0067 1.11 0.256 2394 0.028 1.08 0.251 3046 C09 rs3211650 91115047 T 0.091 28320 0.00074 1.20 0.107 2394 0.0018 1.17 0.104 3046 C09 rs3211683 91119689 A 0.090 28319 0.00071 1.20 0.107 2395 0.0019 1.17 0.104 3047 C09 rs7854755 106902871 A 0.202 28257 0.0036 1.12 0.221 2389 0.008 1.10 0.218 3038 C09 rs4979085 113970927 T 0.296 28305 0.048 1.07 0.311 2392 0.048 1.07 0.309 3044 C09 rs2236388 116209121 G 0.901 28319 0.048 1.12 0.910 2395 0.01 1.14 0.912 3047 C09 rs3780680 125819315 T 0.456 28295 0.021 1.08 0.475 2393 0.037 1.06 0.471 3045 C09 rs7026302 132818296 G 0.909 28320 0.001 1.22 0.924 2395 0.018 1.13 0.919 3047 C09 rs4917341 136289075 C 0.479 28257 0.00013 1.13 0.510 2392 0.000018 1.14 0.510 3041 C09 rs1930788 136303539 C 0.250 28321 0.0022 1.12 0.272 2395 0.0049 1.10 0.268 3047 C09 rs2297538 138684489 G 0.730 28226 0.0012 1.13 0.753 2395 0.00079 1.12 0.752 3047 C09 rs2385891 138716241 A 0.547 28259 0.0014 1.11 0.572 2387 0.011 1.08 0.565 3037 C10 rs12776254 2144862 G 0.171 28314 0.0054 1.12 0.189 2395 0.0048 1.11 0.187 3047 C10 rs4880711 5217871 C 0.351 27953 0.042 1.07 0.367 2379 0.26 1.04 0.359 3015 C10 rs7912210 5984421 C 0.963 28273 0.00083 1.37 0.973 2374 0.0009 1.33 0.972 3023 C10 rs541045 8232155 C 0.429 27990 0.00024 1.13 0.459 2351 0.00032 1.11 0.455 3000 C10 rs4747760 8313669 G 0.874 28308 0.0098 1.14 0.888 2395 0.019 1.11 0.885 3047 C10 rs7092384 8340796 C 0.861 28315 0.0091 1.13 0.875 2395 0.011 1.12 0.873 3047 C10 rs1419294 8347160 T 0.710 28320 0.0036 1.11 0.731 2395 0.0045 1.10 0.728 3047 C10 rs10508403 10448081 T 0.091 28314 0.0017 1.19 0.106 2395 0.01 1.14 0.102 3047 C10 rs2138930 15423774 T 0.110 28304 0.0065 1.15 0.124 2395 0.021 1.11 0.120 3046 C10 rs11596590 15455285 T 0.560 28303 0.02 1.08 0.579 2393 0.072 1.06 0.573 3044 C10 rs12269612 15475877 T 0.401 28314 0.0078 1.09 0.423 2395 0.024 1.07 0.418 3047 C10 rs1925819 15492765 T 0.560 28319 0.026 1.08 0.578 2395 0.087 1.05 0.572 3047 C10 rs1013406 15501576 C 0.562 28307 0.024 1.08 0.580 2392 0.087 1.05 0.575 3044 C10 rs2184383 16416276 G 0.807 28313 0.0019 1.14 0.827 2395 0.016 1.10 0.821 3047 C10 rs10828393 23329068 C 0.892 28259 0.0039 1.17 0.906 2392 0.012 1.13 0.903 3043 C10 rs993352 23347212 G 0.885 28271 0.011 1.14 0.898 2384 0.009 1.13 0.897 3032 C10 rs7086207 26227683 G 0.408 28303 0.00068 1.12 0.435 2394 0.0019 1.10 0.430 3046 C10 rs788053 29363574 T 0.747 28203 0.0021 1.12 0.768 2391 0.0029 1.11 0.766 3043 C10 rs7086224 30857283 A 0.419 28287 0.028 1.08 0.437 2393 0.04 1.06 0.434 3045 C10 rs2804453 33708138 G 0.110 28256 0.021 1.12 0.122 2392 0.051 1.09 0.119 3043 C10 rs2279434 45275070 T 0.067 28318 0.0029 1.20 0.080 2395 0.014 1.15 0.076 3047 C10 rs3793786 50413094 C 0.247 28319 0.3 1.04 0.255 2395 0.79 1.01 0.249 3047 C10 rs4948410 61786053 A 0.788 28175 0.15 1.06 0.797 2391 0.4 1.03 0.793 3041 C10 rs990828 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C 0.724 27673 0.037 1.08 0.739 2358 0.03 1.08 0.738 3002 C10 rs10749535 88094506 T 0.478 28319 0.026 1.08 0.496 2395 0.048 1.06 0.492 3047 C10 rs4933391 88111974 A 0.393 28298 0.011 1.09 0.413 2395 0.021 1.07 0.409 3047 C10 rs3814614 88118261 T 0.508 28312 0.013 1.08 0.528 2394 0.013 1.08 0.526 3046 C10 rs1412444 90992907 A 0.361 28293 0.00037 1.13 0.389 2394 0.0014 1.10 0.383 3045 C10 rs2243548 91000293 A 0.512 28294 0.0007 1.12 0.540 2392 0.0087 1.08 0.532 3043 C10 rs2243547 91000459 G 0.331 28033 0.000027 1.15 0.363 2386 0.00066 1.11 0.355 3033 C10 rs1028935 93339072 A 0.189 28316 0.15 1.06 0.199 2395 0.25 1.04 0.196 3047 C10 rs10509657 95166923 C 0.103 28305 0.024 1.12 0.115 2395 0.078 1.09 0.111 3047 C10 rs10509680 96724329 T 0.052 28256 0.064 1.14 0.059 2389 0.17 1.09 0.057 3039 C10 rs1539089 102211414 C 0.224 28318 0.027 1.09 0.239 2395 0.0086 1.10 0.240 3047 C10 rs11190578 102228943 T 0.224 28317 0.027 1.09 0.239 2395 0.0085 1.10 0.240 3047 C10 rs9420802 102341775 G 0.210 11411 0.0064 1.14 0.232 1773 0.0074 1.13 0.230 2092 C10 rs4630219 102472174 C 0.099 11332 0.008 1.18 0.115 1768 0.012 1.16 0.113 2083 C10 rs11192557 107442673 T 0.878 28251 0.017 1.13 0.890 2390 0.019 1.11 0.889 3040 C10 rs1337430 108996443 A 0.796 28310 0.2 1.05 0.804 2392 0.25 1.04 0.803 3044 C10 rs1557227 119643657 C 0.859 28316 0.0093 1.13 0.873 2394 0.0018 1.15 0.874 3046 C10 rs7922488 120006858 G 0.536 28291 0.022 1.08 0.554 2385 0.051 1.06 0.550 3037 C10 rs2935689 123476616 C 0.839 28314 0.00098 1.16 0.858 2395 0.013 1.11 0.852 3047 C10 rs2936875 123481633 T 0.782 28304 0.00031 1.16 0.806 2394 0.0031 1.11 0.800 3046 C10 rs2239586 124239225 T 0.119 28306 0.0046 1.15 0.134 2395 0.011 1.12 0.131 3047 C10 rs639079 132085590 G 0.192 27862 0.00062 1.15 0.214 2354 0.0009 1.13 0.211 2998 C10 rs11597160 132163778 A 0.907 28320 0.0034 1.19 0.920 2395 0.015 1.14 0.917 3047 C10 rs1484652 132164140 T 0.906 28319 0.002 1.20 0.920 2395 0.0092 1.15 0.917 3047 C10 rs893504 132859084 C 0.073 28315 0.021 1.15 0.082 2395 0.0064 1.16 0.083 3047 C11 rs7122936 1331032 A 0.576 28230 0.00078 1.12 0.603 2395 0.0013 1.10 0.600 3046 C11 rs7944761 1361414 T 0.532 28309 0.0053 1.10 0.555 2395 0.0027 1.09 0.554 3047 C11 rs4963076 1379752 T 0.481 28301 0.011 1.09 0.502 2395 0.04 1.06 0.496 3047 C11 rs11041390 7432565 A 0.730 28304 0.0048 1.11 0.750 2394 0.013 1.09 0.746 3046 C11 rs7113222 7437034 G 0.740 28315 0.0037 1.12 0.760 2395 0.015 1.09 0.755 3047 C11 rs12292613 7580592 T 0.890 28149 0.0001 1.24 0.910 2362 0.00018 1.20 0.907 3011 C11 rs10500734 10898494 A 0.771 28271 0.006 1.12 0.789 2385 0.025 1.08 0.785 3035 C11 rs3935878 12963973 T 0.740 28267 0.000093 1.16 0.767 2392 0.00024 1.13 0.763 3039 C11 rs10832223 14142269 T 0.841 28293 0.083 1.08 0.851 2395 0.046 1.09 0.851 3047 C11 rs7946133 17748398 T 0.914 28127 0.02 1.15 0.925 2332 0.12 1.09 0.920 2977 C11 rs2237921 17894230 C 0.159 28318 0.0049 1.13 0.176 2395 0.014 1.10 0.172 3046 C11 rs3993323 17910658 A 0.143 28305 0.004 1.14 0.160 2392 0.0089 1.11 0.157 3043 C11 rs920671 20006628 A 0.187 28318 0.11 1.07 0.197 2395 0.2 1.05 0.195 3047 C11 rs920675 20006846 A 0.363 28319 0.0039 1.10 0.386 2394 0.0041 1.09 0.383 3046 C11 rs10836066 33455044 T 0.303 28316 0.00026 1.14 0.330 2395 0.042 1.07 0.317 3046 C11 rs1532096 42869929 T 0.860 28317 0.0012 1.17 0.878 2395 0.0024 1.14 0.875 3047 C11 rs7939657 42934015 T 0.557 28307 0.021 1.08 0.575 2395 0.018 1.07 0.574 3047 C11 rs10838271 44341504 C 0.216 28257 0.019 1.10 0.232 2392 0.034 1.08 0.229 3042 C11 rs717117 56651181 G 0.077 28317 0.037 1.13 0.086 2395 0.048 1.11 0.085 3047 C11 rs1005858 68613492 G 0.471 28318 0.0019 1.11 0.496 2395 0.015 1.07 0.489 3047 C11 rs7111999 68617234 G 0.471 27937 0.0018 1.11 0.496 2354 0.013 1.08 0.489 2996 C11 rs2924536 68626681 A 0.448 28308 0.0024 1.10 0.473 2394 0.012 1.08 0.467 3046 C11 rs4623925 82740177 A 0.270 28306 0.0021 1.12 0.293 2395 0.013 1.09 0.287 3047 C11 rs2163612 82856844 G 0.479 28294 0.000001 1.17 0.519 2393 0.0000036 1.15 0.513 3045 C11 rs7952084 83059967 A 0.358 28300 0.0018 1.11 0.382 2395 0.0061 1.09 0.377 3046 C11 rs1436622 90698546 A 0.686 28303 0.00056 1.13 0.712 2395 0.00023 1.13 0.711 3047 C11 rs2568712 91046953 T 0.389 28264 0.00072 1.12 0.416 2392 0.014 1.08 0.407 3043 C11 rs808003 91127230 T 0.554 28317 0.0003 1.13 0.583 2395 0.0053 1.09 0.574 3047 C11 rs9971402 92396199 C 0.872 28196 0.0066 1.15 0.887 2388 0.034 1.10 0.882 3038 C11 rs2658801 92856399 A 0.273 28317 0.023 1.09 0.290 2395 0.004 1.10 0.292 3047 C11 rs1039953 97062996 C 0.680 28302 0.011 1.09 0.700 2395 0.0066 1.09 0.699 3047 C11 rs7120353 98546758 T 0.903 28289 0.036 1.13 0.913 2395 0.017 1.13 0.914 3047 C11 rs1461684 98601689 T 0.854 28312 0.072 1.09 0.864 2395 0.045 1.09 0.864 3047 C11 rs11225090 101337818 T 0.966 28172 0.00053 1.42 0.976 2340 0.0024 1.31 0.974 2989 C11 rs1276252 102039767 G 0.255 28318 0.031 1.08 0.270 2395 0.09 1.06 0.266 3047 C11 rs719527 102945919 C 0.236 28278 0.019 1.09 0.252 2395 0.045 1.07 0.248 3047 C11 rs10502020 103220691 G 0.449 28319 0.0071 1.09 0.471 2395 0.0056 1.09 0.469 3046 C11 rs1509729 108432693 G 0.691 28318 0.0051 1.11 0.712 2395 0.0074 1.09 0.709 3047 C11 rs11604632 110013250 A 0.173 28295 0.001 1.15 0.194 2395 0.000026 1.17 0.197 3045 C11 rs531743 121625352 A 0.955 28306 0.00062 1.34 0.966 2393 0.0032 1.25 0.964 3045 C11 rs4936757 122257924 C 0.567 28307 0.011 1.09 0.588 2395 0.0084 1.08 0.587 3047 C11 rs7933433 127699660 G 0.648 28312 0.0055 1.10 0.670 2394 0.006 1.09 0.668 3046 C11 rs1395504 132234377 A 0.497 28319 0.033 1.07 0.514 2395 0.031 1.07 0.513 3047 C11 rs1289455 134148357 T 0.150 28259 0.0013 1.15 0.169 2391 0.00055 1.15 0.169 3042 C11 rs1289450 134151851 A 0.198 28099 0.00044 1.15 0.222 2390 0.00015 1.15 0.221 3039 C12 rs797773 6177827 T 0.401 28283 0.00077 1.12 0.428 2393 0.0082 1.08 0.420 3044 C12 rs2160424 9180220 G 0.556 28256 0.00048 1.12 0.585 2384 0.0016 1.10 0.579 3035 C12 rs3213831 9208040 T 0.547 28320 0.019 1.08 0.566 2395 0.012 1.08 0.566 3047 C12 rs3782677 9208670 C 0.548 28320 0.017 1.08 0.567 2395 0.011 1.08 0.566 3047 C12 rs9805106 19263624 G 0.822 28153 0.021 1.11 0.836 2380 0.0052 1.12 0.838 3028 C12 rs10743315 19360345 G 0.882 28166 0.023 1.13 0.894 2384 0.017 1.12 0.893 3035 C12 rs2417821 20081535 T 0.754 28317 0.014 1.10 0.771 2395 0.0042 1.11 0.772 3047 C12 rs11045018 20118148 G 0.752 28298 0.01 1.10 0.770 2394 0.0071 1.10 0.769 3046 C12 rs7299937 20196656 T 0.060 28243 0.0014 1.23 0.073 2394 0.0079 1.17 0.069 3045 C12 rs3764006 20945636 C 0.104 28304 0.022 1.13 0.116 2395 0.022 1.11 0.115 3047 C12 rs1910186 21065184 C 0.111 28301 0.01 1.14 0.124 2395 0.02 1.11 0.122 3047 C12 rs11045689 21092930 G 0.301 28210 0.017 1.09 0.319 2386 0.015 1.08 0.317 3037 C12 rs2955503 22090132 A 0.655 28289 0.00054 1.13 0.681 2394 0.000033 1.14 0.684 3045 C12 rs2171392 22797592 A 0.196 28289 0.0068 1.12 0.213 2394 0.011 1.10 0.211 3045 C12 rs16925384 22807863 A 0.195 28302 0.0069 1.12 0.213 2394 0.0098 1.10 0.210 3046 C12 rs12425518 47206273 A 0.046 28295 0.031 1.17 0.054 2392 0.15 1.10 0.051 3042 C12 rs12581026 47223943 C 0.048 28310 0.0073 1.21 0.058 2394 0.059 1.13 0.054 3046 C12 rs784563 52152886 G 0.445 28308 0.049 1.07 0.461 2395 0.12 1.05 0.457 3047 C12 rs6580960 52445647 A 0.544 28320 0.068 1.06 0.558 2395 0.06 1.06 0.557 3047 C12 rs10878126 62930978 G 0.495 28299 0.016 1.08 0.515 2395 0.017 1.07 0.513 3046 C12 rs1465026 65789635 G 0.837 28309 0.011 1.12 0.852 2395 0.024 1.10 0.849 3047 C12 rs1526839 65801361 G 0.837 28240 0.019 1.11 0.851 2392 0.037 1.09 0.848 3042 C12 rs11835794 65812323 T 0.858 28321 0.056 1.10 0.868 2395 0.095 1.07 0.866 3047 C12 rs1470383 67493429 C 0.144 28320 0.0068 1.13 0.160 2395 0.0065 1.12 0.159 3047 C12 rs2584019 69318052 T 0.889 11415 0.00091 1.24 0.909 1775 0.0015 1.21 0.907 2094 C12 rs7978668 69325443 T 0.917 28319 0.0043 1.19 0.929 2395 0.0082 1.16 0.927 3047 C12 rs767760 69326403 A 0.914 28320 0.0041 1.19 0.927 2395 0.0068 1.16 0.925 3047 C12 rs7309888 69340682 C 0.794 28317 0.0034 1.13 0.813 2395 0.00095 1.13 0.814 3047 C12 rs7976576 69347673 T 0.795 28318 0.0049 1.12 0.813 2395 0.0015 1.13 0.813 3046 C12 rs949664 69368222 A 0.860 28228 0.0019 1.16 0.878 2393 0.0015 1.15 0.876 3043 C12 rs7135414 75996159 A 0.917 28317 0.0074 1.18 0.928 2395 0.0029 1.18 0.928 3047 C12 rs1401875 87986337 T 0.058 28291 0.095 1.12 0.064 2392 0.056 1.12 0.065 3041 C12 rs1568383 88017285 T 0.098 28316 0.008 1.15 0.111 2395 0.0049 1.14 0.110 3045 C12 rs11108788 95989532 G 0.036 27597 0.0085 1.24 0.044 2388 0.035 1.17 0.041 3040 C12 rs989264 96044433 A 0.044 28316 0.14 1.12 0.049 2395 0.18 1.10 0.049 3047 C12 rs7135604 96910191 A 0.657 28303 0.0022 1.11 0.680 2394 0.0076 1.09 0.676 3045 C12 rs864302 100490144 T 0.483 28309 0.033 1.07 0.501 2395 0.035 1.06 0.499 3047 C12 rs12311520 101693527 C 0.870 28247 0.09 1.09 0.879 2395 0.23 1.06 0.876 3046 C12 rs2247919 101699389 T 0.742 28307 0.071 1.07 0.755 2395 0.28 1.04 0.749 3046 C12 rs1015249 111609694 C 0.692 28316 0.0002 1.14 0.720 2395 0.00038 1.12 0.716 3046 C12 rs1293758 111917970 A 0.408 28316 0.0027 1.10 0.432 2394 0.0041 1.09 0.429 3046 C12 rs249047 112562237 A 0.614 28289 0.000091 1.14 0.645 2392 0.0015 1.10 0.637 3044 C12 rs1920947 114285453 C 0.810 28301 0.012 1.11 0.826 2394 0.014 1.10 0.824 3046 C12 rs816204 116492124 A 0.855 28175 0.0023 1.16 0.872 2384 0.0033 1.14 0.870 3034 C12 rs4767629 116739460 T 0.140 28316 0.025 1.11 0.153 2395 0.06 1.08 0.150 3047 C12 rs2592289 116759379 A 0.156 28311 0.0039 1.13 0.173 2395 0.0013 1.14 0.173 3047 C12 rs719450 119438416 C 0.918 28320 0.024 1.15 0.928 2394 0.019 1.14 0.928 3046 C12 rs3742049 119438873 C 0.919 28300 0.029 1.14 0.928 2394 0.023 1.13 0.928 3046 C12 rs1169081 120890295 C 0.693 28306 0.0032 1.11 0.715 2394 0.06 1.06 0.706 3045 C12 rs7979863 121629420 A 0.380 28309 0.022 1.08 0.399 2395 0.0025 1.10 0.402 3047 C12 rs10847227 121632638 T 0.279 28258 0.012 1.09 0.297 2395 0.00028 1.12 0.303 3047 C12 rs4765477 123287223 T 0.045 28300 0.016 1.20 0.053 2395 0.023 1.17 0.052 3047 C12 rs3759107 123548064 T 0.127 28320 0.023 1.11 0.139 2395 0.014 1.11 0.139 3047 C12 rs12304836 124654446 C 0.143 28205 0.00054 1.17 0.163 2385 0.00095 1.14 0.160 3034 C12 rs7310042 124675580 G 0.192 28317 0.018 1.10 0.207 2395 0.0043 1.11 0.209 3047 C12 rs470477 128010541 T 0.311 28306 0.0061 1.10 0.332 2395 0.013 1.08 0.328 3046 C13 rs4770252 21699475 A 0.806 28293 0.0088 1.12 0.822 2394 0.016 1.10 0.819 3044 C13 rs9285207 21722774 C 0.200 28256 0.0015 1.13 0.220 2387 0.0061 1.10 0.216 3037 C13 rs1887263 22381716 A 0.204 28175 0.067 1.08 0.216 2393 0.037 1.08 0.217 3042 C13 rs4769613 28036609 T 0.465 28313 0.00041 1.12 0.494 2394 0.00013 1.12 0.493 3046 C13 rs9566343 38000184 T 0.814 28309 0.011 1.11 0.830 2395 0.013 1.10 0.828 3046 C13 rs9315759 39616680 C 0.132 28308 0.0045 1.14 0.147 2394 0.0045 1.13 0.146 3046 C13 rs9525923 43681715 A 0.210 28320 0.00015 1.16 0.236 2395 0.0019 1.12 0.229 3047 C13 rs963569 44140379 A 0.753 28315 0.0074 1.11 0.771 2395 0.037 1.08 0.766 3047 C13 rs7322927 46552894 A 0.129 28318 0.021 1.12 0.142 2395 0.059 1.09 0.139 3047 C13 rs9534568 46693565 A 0.769 11414 0.086 1.08 0.783 1775 0.094 1.08 0.782 2094 C13 rs9526329 46866462 G 0.922 28290 0.00038 1.26 0.937 2395 0.0067 1.17 0.933 3047 C13 rs2050972 54308642 C 0.881 28309 0.01 1.14 0.894 2395 0.011 1.13 0.893 3047 C13 rs1993776 54406486 C 0.872 28309 0.011 1.14 0.885 2395 0.011 1.12 0.884 3047 C13 rs17070671 67943127 T 0.830 28318 0.00076 1.16 0.850 2395 0.017 1.10 0.843 3047 C13 rs1375719 102208783 C 0.499 28316 0.032 1.07 0.517 2394 0.12 1.05 0.511 3046 C13 rs2038709 102370990 C 0.084 28237 0.0084 1.16 0.096 2393 0.038 1.11 0.093 3045 C13 rs1347329 104032541 C 0.592 11392 0.005 1.12 0.619 1775 0.031 1.09 0.612 2093 C13 rs354438 105737486 T 0.355 28306 0.12 1.05 0.367 2395 0.33 1.03 0.362 3047 C13 rs1927771 106592839 A 0.416 28317 0.05 1.07 0.432 2395 0.078 1.05 0.429 3046 C13 rs1163852 110962872 C 0.713 28319 0.0031 1.11 0.735 2395 0.0056 1.10 0.732 3046 C14 rs10872856 20356515 C 0.914 28314 0.04 1.13 0.923 2395 0.022 1.13 0.923 3047 C14 rs991387 32384515 G 0.803 28319 0.026 1.10 0.818 2394 0.047 1.08 0.815 3046 C14 rs1950216 32385175 T 0.803 28318 0.027 1.10 0.818 2395 0.048 1.08 0.815 3047 C14 rs1742655 45622604 C 0.885 28321 0.0015 1.19 0.901 2395 0.0049 1.14 0.898 3047 C14 rs8007161 49042790 T 0.886 28278 0.027 1.12 0.898 2393 0.085 1.09 0.894 3044 C14 rs12436454 49076076 T 0.717 28226 0.0028 1.12 0.738 2393 0.012 1.09 0.733 3044 C14 rs4898630 49269010 A 0.878 28293 0.0079 1.15 0.892 2394 0.022 1.11 0.889 3046 C14 rs1458114 52093597 T 0.706 27829 0.0005 1.14 0.732 2338 0.0043 1.10 0.725 2979 C14 rs4444235 53480669 T 0.536 28305 0.37 1.03 0.543 2394 0.32 1.03 0.543 3046 C14 rs1957860 53499105 T 0.448 28313 0.27 0.97 0.439 2395 0.55 0.98 0.444 3047 C14 rs392030 58368609 G 0.636 28319 0.015 1.09 0.654 2395 0.029 1.07 0.651 3047 C14 rs2069334 58368941 A 0.188 28314 0.043 1.09 0.201 2395 0.099 1.06 0.197 3047 C14 rs17095237 58383406 G 0.164 28314 0.056 1.09 0.176 2395 0.17 1.06 0.172 3046 C14 rs10483707 58477558 A 0.141 28319 0.054 1.09 0.152 2395 0.14 1.06 0.148 3047 C14 rs11158238 58517378 T 0.142 28317 0.06 1.09 0.153 2395 0.11 1.07 0.150 3047 C14 rs7147624 64935378 G 0.801 28311 0.011 1.11 0.817 2395 0.034 1.08 0.813 3046 C14 rs2411822 64948148 C 0.486 28314 0.024 1.08 0.505 2395 0.11 1.05 0.498 3047 C14 rs1953416 64948560 T 0.483 28267 0.016 1.08 0.503 2391 0.073 1.05 0.497 3042 C14 rs7145500 64953965 A 0.663 28319 0.031 1.08 0.679 2395 0.05 1.06 0.676 3047 C14 rs12433694 65380138 C 0.483 28319 0.031 1.07 0.500 2395 0.1 1.05 0.494 3047 C14 rs1147443 65538514 T 0.251 28316 0.000014 1.17 0.282 2395 0.0000074 1.16 0.280 3047 C14 rs1147437 65544105 G 0.380 28316 0.000065 1.14 0.412 2395 0.000058 1.13 0.409 3046 C14 rs894921 65546005 G 0.376 28318 0.000056 1.14 0.408 2395 0.000054 1.13 0.405 3047 C14 rs6573648 65617378 G 0.272 28316 0.000041 1.16 0.302 2395 0.000028 1.15 0.300 3047 C14 rs17754686 65667738 A 0.307 28239 0.00015 1.14 0.335 2392 0.00007 1.13 0.334 3044 C14 rs8003722 68388015 A 0.106 28317 0.0085 1.14 0.119 2394 0.024 1.11 0.116 3046 C14 rs1291302 69449823 C 0.265 28043 0.13 1.06 0.276 2363 0.22 1.04 0.273 3015 C14 rs10498639 93845279 A 0.428 28316 0.0088 1.09 0.449 2395 0.018 1.07 0.445 3047 C14 rs2281519 93846385 T 0.260 28281 0.0023 1.12 0.282 2395 0.014 1.09 0.276 3045 C14 rs2895811 99203695 C 0.449 28199 0.0018 1.11 0.474 2385 0.0015 1.10 0.472 3033 C14 rs7158073 99211442 T 0.430 28102 0.0005 1.12 0.458 2379 0.0016 1.10 0.453 3027 C14 rs12435918 99240648 G 0.333 28318 0.0006 1.12 0.359 2395 0.0016 1.10 0.355 3047 C14 rs2273840 99257897 A 0.931 28124 0.0031 1.22 0.943 2369 0.0035 1.20 0.941 3019 C14 rs17776453 100774793 G 0.955 28313 0.095 1.15 0.961 2394 0.033 1.17 0.962 3045 C14 rs4708 102469201 A 0.549 28293 0.007 1.09 0.571 2393 0.019 1.07 0.566 3043 C14 rs10129841 102473912 A 0.578 28316 0.0014 1.11 0.604 2395 0.012 1.08 0.596 3047 C14 rs8016595 103791279 C 0.756 28304 0.016 1.10 0.773 2395 0.04 1.07 0.769 3047 C15 rs4572353 24287601 T 0.498 28314 0.0003 1.13 0.528 2393 0.00013 1.12 0.526 3043 C15 rs2110209 24946433 A 0.048 28318 0.00051 1.28 0.061 2395 0.0061 1.20 0.057 3047 C15 rs4779984 30302218 G 0.100 28236 0.0015 1.18 0.116 2392 0.003 1.15 0.114 3043 C15 rs7183966 34836718 G 0.129 28307 0.00037 1.18 0.149 2393 0.0032 1.13 0.144 3044 C15 rs1901725 34837201 T 0.129 28318 0.00038 1.18 0.149 2395 0.0034 1.13 0.144 3047 C15 rs1194620 34902036 T 0.233 28268 0.0084 1.11 0.251 2394 0.042 1.07 0.246 3044 C15 rs1841441 37167818 A 0.471 28308 0.021 1.08 0.489 2393 0.0055 1.09 0.491 3045 C15 rs7172161 43778072 G 0.517 28267 0.067 1.06 0.532 2393 0.045 1.06 0.532 3045 C15 rs11630033 43850557 C 0.902 28204 0.065 1.11 0.911 2389 0.1 1.09 0.909 3040 C15 rs1156234 51156742 G 0.795 28314 0.0028 1.13 0.815 2395 0.0077 1.10 0.811 3047 C15 rs2553223 52657225 G 0.344 28301 0.000086 1.14 0.375 2395 0.00015 1.12 0.371 3047 C15 rs2414325 52675829 T 0.489 28318 0.00012 1.13 0.520 2395 0.00022 1.12 0.516 3047 C15 rs8041044 53452605 C 0.915 28200 0.015 1.16 0.925 2389 0.044 1.12 0.923 3039 C15 rs4775234 58117938 C 0.259 27735 0.0047 1.11 0.280 2354 0.031 1.08 0.273 2995 C15 rs11072793 76793497 G 0.231 28268 0.00025 1.15 0.257 2388 0.0013 1.12 0.251 3040 C15 rs4255747 77512872 G 0.677 28311 0.07 1.07 0.691 2395 0.24 1.04 0.685 3047 C15 rs4887480 84366589 G 0.771 28306 0.0014 1.13 0.793 2395 0.0051 1.11 0.788 3045 C15 rs12595195 88001739 C 0.280 28292 0.0093 1.10 0.299 2395 0.056 1.06 0.292 3046 C15 rs3743369 90508573 T 0.616 28313 0.032 1.07 0.633 2394 0.029 1.07 0.632 3046 C15 rs6496899 90511768 C 0.766 28152 0.02 1.10 0.781 2375 0.014 1.09 0.781 3024 C15 rs10152962 92112175 G 0.153 28319 0.014 1.11 0.168 2393 0.0078 1.11 0.167 3045 C15 rs176656 93537286 A 0.093 28317 0.054 1.11 0.103 2395 0.055 1.10 0.102 3047 C15 rs7177625 95764563 G 0.687 28300 0.029 1.08 0.703 2395 0.16 1.05 0.696 3046 C15 rs2684790 97309063 T 0.146 28314 0.0036 1.14 0.163 2395 0.011 1.11 0.160 3047 C16 rs8057913 2009168 C 0.266 28244 0.0066 1.10 0.286 2391 0.0057 1.10 0.285 3042 C16 rs2286472 2010569 C 0.271 28249 0.011 1.10 0.290 2385 0.007 1.09 0.289 3036 C16 rs8045288 2013121 T 0.269 28279 0.01 1.10 0.287 2394 0.0082 1.09 0.286 3045 C16 rs3785284 2014037 C 0.267 28138 0.012 1.10 0.285 2384 0.009 1.09 0.284 3032 C16 rs8053779 18979415 G 0.738 28314 0.12 1.06 0.749 2395 0.13 1.05 0.748 3047 C16 rs7500550 18985697 G 0.782 28319 0.065 1.08 0.794 2394 0.045 1.08 0.794 3046 C16 rs1634675 19801122 G 0.789 28308 0.023 1.10 0.804 2395 0.054 1.07 0.800 3047 C16 rs8050136 52373776 A 0.404 28316 0.0046 1.10 0.426 2394 0.00029 1.11 0.430 3046 C16 rs3751812 52375961 T 0.403 28246 0.0041 1.10 0.426 2392 0.00024 1.12 0.430 3044 C16 rs1033043 52774858 T 0.577 28311 0.027 1.08 0.594 2394 0.052 1.06 0.591 3046 C16 rs2665282 52779886 A 0.577 28267 0.029 1.07 0.594 2391 0.059 1.06 0.591 3041 C16 rs12924635 60072235 G 0.397 27765 0.0043 1.10 0.420 2306 0.023 1.07 0.414 2944 C16 rs2962080 61410292 G 0.609 28310 0.0056 1.10 0.631 2394 0.06 1.06 0.623 3046 C16 rs7192142 62724486 T 0.810 28254 0.00063 1.16 0.832 2385 0.0059 1.11 0.826 3036 C16 rs12927636 72310379 G 0.108 28296 0.0028 1.16 0.123 2393 0.0065 1.13 0.121 3045 C16 rs1038864 72320058 C 0.185 28319 0.012 1.11 0.201 2395 0.019 1.09 0.198 3047 C16 rs4243110 73810027 T 0.462 28299 0.01 1.09 0.482 2394 0.0043 1.09 0.482 3046 C16 rs1862737 73839465 C 0.484 28309 0.0017 1.11 0.509 2395 0.0013 1.10 0.508 3046 C16 rs7188879 78364890 T 0.966 28303 0.048 1.21 0.972 2394 0.11 1.14 0.970 3046 C16 rs1870843 81316815 T 0.602 28313 0.0081 1.09 0.623 2395 0.0098 1.08 0.621 3047 C16 rs10514560 81328576 C 0.734 28315 0.011 1.10 0.752 2395 0.022 1.08 0.749 3047 C16 rs4075964 86985334 A 0.283 28229 0.0063 1.10 0.304 2392 0.016 1.08 0.299 3042 C16 rs904800 87044441 G 0.383 28296 0.0057 1.10 0.405 2395 0.0062 1.09 0.403 3045 C17 rs4130140 257873 A 0.174 28319 0.00063 1.15 0.195 2395 0.0027 1.12 0.191 3047 C17 rs4791759 7618652 A 0.041 28305 0.065 1.16 0.047 2394 0.32 1.07 0.044 3044 C17 rs3891720 9331114 C 0.872 28298 0.0034 1.16 0.888 2392 0.026 1.11 0.883 3044 C17 rs9903582 10175559 C 0.749 28317 0.01 1.10 0.767 2395 0.022 1.08 0.764 3047 C17 rs12449610 13998813 T 0.669 28319 0.0025 1.11 0.692 2395 0.0087 1.09 0.687 3047 C17 rs2323095 14000644 A 0.664 28312 0.0027 1.11 0.687 2395 0.013 1.08 0.681 3047 C17 rs2856177 14041754 A 0.622 28308 0.0085 1.09 0.642 2395 0.016 1.08 0.639 3047 C17 rs4401079 16755421 T 0.211 27570 0.028 1.09 0.226 2340 0.015 1.09 0.226 2975 C17 rs4925108 17590148 C 0.394 28297 0.0015 1.11 0.420 2394 0.014 1.08 0.412 3046 C17 rs752579 17601072 G 0.390 28286 0.0051 1.10 0.412 2394 0.043 1.06 0.404 3046 C17 rs4925109 17602527 A 0.318 28316 0.00032 1.13 0.345 2395 0.0045 1.09 0.337 3047 C17 rs11649804 17637480 A 0.292 28148 0.00029 1.14 0.319 2341 0.0041 1.10 0.312 2987 C17 rs4925114 17651995 A 0.357 28266 0.000045 1.15 0.389 2391 0.0017 1.10 0.379 3042 C17 rs11868035 17655826 A 0.294 28278 0.000068 1.15 0.324 2393 0.0016 1.11 0.315 3043 C17 rs9902941 17674485 C 0.347 28319 0.0000029 1.17 0.384 2395 0.00095 1.11 0.371 3047 C17 rs4925119 17683629 A 0.345 28218 0.0000077 1.16 0.380 2387 0.0021 1.10 0.367 3036 C17 rs3183702 17688014 T 0.348 28108 0.0000041 1.17 0.384 2388 0.0013 1.10 0.371 3038 C17 rs4925125 17735169 T 0.353 28060 0.0000082 1.16 0.388 2374 0.0016 1.10 0.376 3021 C17 rs6502622 17775416 G 0.358 28303 0.0000065 1.16 0.393 2395 0.0019 1.10 0.380 3047 C17 rs2955355 17889200 C 0.285 28312 0.00000087 1.19 0.321 2395 0.00033 1.12 0.309 3047 C17 rs854813 17944570 C 0.385 28182 0.000011 1.16 0.420 2393 0.0031 1.09 0.406 3042 C17 rs854793 17971249 A 0.202 28313 0.000033 1.18 0.229 2395 0.0018 1.12 0.220 3047 C17 rs854787 17975744 C 0.400 28104 0.000046 1.14 0.432 2381 0.0046 1.09 0.420 3028 C17 rs854771 18000917 C 0.554 28297 0.00061 1.12 0.581 2395 0.00086 1.10 0.578 3046 C17 rs2746025 18092336 G 0.640 28315 0.0001 1.14 0.670 2394 0.0013 1.11 0.663 3046 C17 rs9911448 21030674 C 0.961 28319 0.023 1.23 0.968 2395 0.083 1.15 0.966 3047 C17 rs7210156 34250987 G 0.929 28256 0.0024 1.23 0.941 2392 0.019 1.15 0.937 3043 C17 rs1122326 37528399 C 0.242 28309 0.00086 1.13 0.265 2395 0.02 1.08 0.257 3047 C17 rs12603327 37544078 C 0.242 28318 0.00093 1.13 0.265 2395 0.021 1.08 0.256 3047 C17 rs7214921 37547551 C 0.242 28291 0.00095 1.13 0.265 2394 0.021 1.08 0.256 3045 C17 rs4794128 45727464 A 0.276 28309 0.0061 1.10 0.296 2395 0.0081 1.09 0.293 3047 C17 rs11656018 48969375 C 0.707 28240 0.0012 1.13 0.731 2394 0.002 1.11 0.728 3045 C17 rs9895713 50752149 G 0.178 28297 0.013 1.11 0.194 2395 0.03 1.09 0.191 3047 C17 rs1985961 59470994 C 0.413 28311 0.014 1.09 0.433 2395 0.0086 1.08 0.432 3047 C17 rs312750 65855134 C 0.548 28314 0.0018 1.11 0.573 2395 0.019 1.07 0.565 3047 C17 rs9911654 67172007 T 0.899 28314 0.0099 1.16 0.912 2395 0.037 1.11 0.908 3047 C17 rs2041088 67702720 A 0.722 28312 0.0041 1.11 0.743 2395 0.0028 1.11 0.741 3047 C17 rs2159010 67708572 A 0.730 28262 0.0097 1.10 0.748 2395 0.0053 1.10 0.748 3045 C17 rs191227 69202771 A 0.579 28300 0.022 1.08 0.597 2394 0.043 1.06 0.594 3046 C17 rs1000299 70660148 A 0.055 28315 0.0044 1.21 0.066 2394 0.015 1.16 0.063 3046 C17 rs17674253 74732189 A 0.583 28311 0.032 1.07 0.600 2393 0.071 1.06 0.596 3045 C18 rs1791098 3294629 C 0.763 28318 0.022 1.09 0.779 2395 0.24 1.04 0.770 3047 C18 rs12964045 13442635 C 0.131 28312 0.015 1.12 0.145 2394 0.031 1.10 0.142 3046 C18 rs4271662 26051291 C 0.587 28256 0.061 1.06 0.602 2390 0.092 1.05 0.599 3039 C18 rs12964741 35159625 A 0.668 28119 0.0049 1.10 0.689 2359 0.0013 1.11 0.690 3008 C18 rs1015735 39877321 C 0.267 28220 0.035 1.08 0.283 2387 0.15 1.05 0.277 3037 C18 rs4340393 39884052 T 0.266 28320 0.033 1.08 0.282 2395 0.13 1.05 0.276 3047 C18 rs17734724 43268749 G 0.276 28318 0.00071 1.13 0.300 2395 0.0024 1.10 0.296 3047 C18 rs1790778 45715039 G 0.512 28314 0.00027 1.13 0.541 2394 0.000024 1.13 0.543 3046 C18 rs1557359 45734896 G 0.408 28317 0.00063 1.12 0.435 2395 0.00016 1.12 0.435 3047 C18 rs634285 53273824 G 0.913 11415 0.00075 1.28 0.930 1775 0.0036 1.22 0.927 2094 C18 rs580647 53284831 A 0.886 28267 0.034 1.12 0.897 2394 0.057 1.09 0.895 3045 C18 rs4940582 53743264 G 0.851 28314 0.0016 1.16 0.869 2394 0.0016 1.14 0.867 3046 C18 rs657773 55097571 C 0.556 28318 0.00062 1.12 0.583 2395 0.012 1.08 0.574 3047 C18 rs4806 55146376 C 0.285 28175 0.016 1.09 0.303 2376 0.049 1.07 0.299 3025 C18 rs9319948 55193376 A 0.285 28174 0.025 1.08 0.302 2387 0.074 1.06 0.297 3033 C18 rs8088514 55213078 C 0.461 28276 0.0093 1.09 0.482 2386 0.037 1.06 0.476 3038 C18 rs8082768 55792708 T 0.182 28281 0.007 1.12 0.200 2390 0.01 1.10 0.197 3040 C18 rs9948303 55911746 G 0.102 28316 0.084 1.10 0.110 2395 0.0079 1.13 0.114 3047 C18 rs603119 56407631 T 0.391 28278 0.072 1.06 0.406 2394 0.021 1.07 0.408 3045 C18 rs2332026 56572162 A 0.505 28318 0.059 1.06 0.520 2395 0.051 1.06 0.519 3047 C18 rs3744927 58396227 G 0.772 28317 0.0024 1.13 0.793 2395 0.017 1.09 0.787 3047 C18 rs2332575 58449327 A 0.054 28302 0.014 1.18 0.064 2392 0.028 1.15 0.062 3044 C18 rs7241455 58476248 T 0.063 28318 0.0045 1.20 0.075 2395 0.0039 1.18 0.074 3047 C18 rs12458349 58505190 G 0.061 28155 0.0014 1.23 0.074 2389 0.0013 1.21 0.073 3036 C18 rs1365254 70238283 T 0.196 28319 0.066 1.08 0.208 2395 0.036 1.08 0.209 3047 C18 rs4892210 70241069 A 0.196 28316 0.057 1.08 0.209 2395 0.031 1.08 0.209 3047 C18 rs2850889 73087595 C 0.409 28316 0.00013 1.13 0.440 2395 0.00015 1.12 0.437 3046 C18 rs2156643 73088668 G 0.409 28304 0.00013 1.13 0.440 2395 0.00015 1.12 0.436 3047 C18 rs2850892 73088829 C 0.409 28292 0.00014 1.13 0.440 2393 0.00016 1.12 0.436 3043 C19 rs10414677 330003 T 0.285 27883 0.048 1.07 0.299 2322 0.27 1.04 0.292 2956 C19 rs758503 446722 T 0.302 27981 0.012 1.09 0.321 2371 0.011 1.08 0.319 3018 C19 rs4740 4187996 A 0.274 28312 0.017 1.09 0.291 2395 0.054 1.07 0.286 3047 C19 rs1045750 4202069 C 0.269 28318 0.021 1.09 0.286 2394 0.054 1.07 0.281 3046 C19 rs4807567 4229502 T 0.427 28263 0.07 1.06 0.442 2394 0.07 1.06 0.441 3045 C19 rs10419363 4231186 T 0.306 28279 0.076 1.06 0.319 2390 0.069 1.06 0.318 3040 C19 rs10406508 8795907 T 0.764 11415 0.0031 1.15 0.788 1775 0.0092 1.12 0.784 2094 C19 rs7248277 14236895 C 0.570 28306 0.0065 1.09 0.592 2394 0.0034 1.09 0.591 3045 C19 rs2305758 17024661 G 0.691 28308 0.0044 1.11 0.712 2394 0.0026 1.10 0.711 3046 C19 rs2278997 17027981 T 0.229 28315 0.0000018 1.20 0.262 2395 0.0000088 1.16 0.257 3047 C19 rs12459084 17031885 T 0.350 27962 0.00013 1.14 0.380 2387 0.002 1.10 0.372 3037 C19 rs7254154 17039119 C 0.352 28271 0.00019 1.13 0.381 2389 0.0028 1.10 0.373 3041 C19 rs7246865 17080105 A 0.205 28321 0.00016 1.16 0.230 2395 0.00025 1.14 0.227 3047 C19 rs4933027 22695812 T 0.083 28318 0.00019 1.23 0.101 2395 0.0011 1.18 0.097 3047 C19 rs4805463 34828875 G 0.909 28316 0.0018 1.20 0.923 2395 0.0073 1.15 0.920 3047 C19 rs346535 48943265 T 0.234 28317 0.0031 1.12 0.255 2395 0.00078 1.12 0.255 3047 C19 rs377702 50054507 T 0.391 28304 0.007 1.09 0.412 2395 0.014 1.08 0.409 3047 C19 rs3760802 53768499 A 0.505 28309 0.073 1.06 0.519 2392 0.13 1.05 0.516 3044 C19 rs11668495 58638423 C 0.940 28270 0.065 1.14 0.947 2392 0.12 1.11 0.945 3044 C19 rs8113561 62070079 G 0.954 28311 0.0055 1.26 0.963 2395 0.025 1.18 0.960 3047 C20 rs723477 237362 T 0.742 28284 0.004 1.12 0.762 2389 0.0029 1.11 0.761 3040 C20 rs1741285 4064436 G 0.560 28300 0.00075 1.12 0.588 2392 0.00072 1.11 0.585 3043 C20 rs6084644 4069799 G 0.437 28319 0.00096 1.11 0.464 2395 0.00062 1.11 0.462 3047 C20 rs6076623 4084671 T 0.367 28302 0.000045 1.15 0.399 2395 0.0000036 1.15 0.400 3047 C20 rs1741315 4103948 A 0.484 28317 0.0014 1.11 0.510 2395 0.0012 1.10 0.508 3047 C20 rs1741318 4105600 A 0.450 28315 0.0025 1.10 0.474 2394 0.0013 1.10 0.473 3046 C20 rs236110 5881108 G 0.871 28299 0.00079 1.19 0.889 2393 0.0036 1.14 0.885 3044 C20 rs236113 5882566 T 0.883 28321 0.001 1.19 0.900 2395 0.0063 1.14 0.896 3047 C20 rs2026058 13639900 T 0.768 28319 0.048 1.08 0.781 2395 0.084 1.06 0.779 3047 C20 rs6079235 13886789 C 0.736 28308 0.096 1.06 0.748 2394 0.12 1.05 0.746 3046 C20 rs411944 15006882 G 0.651 28275 0.0033 1.11 0.673 2392 0.035 1.07 0.665 3044 C20 rs6034134 15182479 G 0.596 28318 0.026 1.08 0.614 2395 0.065 1.06 0.610 3047 C20 rs199812 22264552 C 0.888 28288 0.0074 1.15 0.902 2394 0.0026 1.16 0.902 3046 C20 rs734484 31943651 C 0.713 28316 0.079 1.07 0.726 2394 0.1 1.06 0.724 3045 C20 rs981303 45947245 A 0.931 28301 0.057 1.14 0.939 2391 0.011 1.17 0.941 3043 C20 rs4811008 48277796 G 0.463 27959 0.00032 1.13 0.493 2348 0.0065 1.09 0.483 2993 C20 rs913670 48339923 C 0.634 28276 0.00081 1.12 0.660 2395 0.0051 1.09 0.654 3046 C20 rs913673 48341447 C 0.541 28304 0.00017 1.13 0.571 2395 0.0029 1.09 0.563 3047 C20 rs6068930 52700213 G 0.040 28199 0.013 1.22 0.048 2389 0.021 1.18 0.046 3039 C20 rs486921 56349782 C 0.854 28319 0.0042 1.15 0.870 2394 0.013 1.11 0.867 3046 C20 rs6128327 56375963 A 0.647 27522 0.029 1.08 0.664 2355 0.079 1.06 0.660 2992 C20 rs6128397 56686538 G 0.690 28315 0.012 1.09 0.708 2395 0.031 1.07 0.704 3047 C20 rs6128843 58519280 T 0.183 28319 0.00057 1.15 0.205 2395 0.0027 1.12 0.201 3047 C21 rs2822391 14334270 A 0.553 28310 0.021 1.08 0.572 2394 0.0088 1.08 0.572 3045 C21 rs2822744 14821123 A 0.158 28318 0.026 1.10 0.171 2395 0.045 1.08 0.169 3047 C21 rs2822753 14824849 G 0.356 28297 0.057 1.07 0.371 2394 0.13 1.05 0.367 3046 C21 rs1349227 16738666 T 0.242 28301 0.018 1.09 0.258 2393 0.021 1.08 0.256 3045 C21 rs2017705 21803122 C 0.074 28287 0.0091 1.17 0.085 2390 0.058 1.11 0.081 3041 C21 rs2828495 24038081 A 0.212 28316 0.001 1.14 0.234 2395 0.00089 1.12 0.232 3047 C21 rs2828515 24056599 G 0.124 28296 0.0093 1.13 0.138 2394 0.0024 1.14 0.139 3046 C21 rs2829040 24693776 A 0.452 28251 0.047 1.07 0.468 2392 0.23 1.04 0.460 3044 C21 rs2830357 26972748 G 0.575 28313 0.0019 1.11 0.600 2395 0.0025 1.10 0.597 3046 C21 rs2251540 26986173 G 0.651 28262 0.0027 1.11 0.674 2391 0.0089 1.09 0.669 3042 C21 rs1882757 40711890 A 0.507 28320 0.079 1.06 0.522 2393 0.068 1.06 0.521 3045 C21 rs3788014 42722104 C 0.925 28314 0.0012 1.24 0.938 2395 0.0019 1.20 0.937 3046 C22 rs2019061 17343340 T 0.689 28294 0.01 1.10 0.708 2388 0.0051 1.09 0.708 3038 C22 rs1978058 18288219 T 0.372 28137 0.000015 1.16 0.406 2388 0.00038 1.11 0.397 3034 C22 rs3804044 18432442 T 0.858 28284 0.0037 1.15 0.875 2395 0.0039 1.13 0.873 3046 C22 rs5992507 18437458 A 0.859 28309 0.004 1.15 0.875 2395 0.0042 1.13 0.873 3047 C22 rs2073778 18454575 C 0.858 28316 0.0036 1.15 0.875 2395 0.0046 1.13 0.873 3047 C22 rs2238798 18487729 G 0.859 28289 0.0045 1.15 0.875 2394 0.0057 1.13 0.873 3044 C22 rs178260 19654308 T 0.142 28310 0.029 1.10 0.154 2395 0.039 1.09 0.152 3047 C22 rs430305 19688522 T 0.829 28319 0.0096 1.12 0.844 2395 0.038 1.09 0.840 3047 C22 rs8135273 32527802 C 0.157 28046 0.025 1.10 0.170 2369 0.057 1.08 0.167 3012 C22 rs2267296 32549939 G 0.444 28313 0.0015 1.11 0.470 2394 0.00076 1.10 0.469 3046 C22 rs2071744 34147553 C 0.782 28278 0.012 1.11 0.798 2394 0.038 1.08 0.794 3044 C22 rs132717 34926598 C 0.618 28303 0.069 1.06 0.633 2395 0.56 1.02 0.622 3047 C22 rs7364143 34932129 T 0.279 28278 0.00042 1.13 0.305 2391 0.0024 1.10 0.299 3043 C22 rs5995259 34941809 A 0.338 28320 0.00058 1.12 0.365 2395 0.004 1.09 0.358 3047 C22 rs763086 34949003 A 0.301 28254 0.0059 1.10 0.322 2391 0.014 1.08 0.318 3038 C22 rs738407 42655288 A 0.640 28301 0.0014 1.12 0.664 2394 0.0018 1.10 0.662 3046 C22 rs739164 45063222 A 0.892 27998 0.0056 1.17 0.906 2330 0.018 1.12 0.903 2978 CX rs6638525 5464517 C 0.110 22852 0.016 1.16 0.126 1545 0.017 1.14 0.124 1962 CX rs1919026 5471853 C 0.195 22929 0.04 1.11 0.212 1550 0.22 1.06 0.204 1967 CX rs7892324 6679297 C 0.167 22905 0.0011 1.19 0.192 1542 0.005 1.14 0.186 1956 CX rs3013140 41283447 G 0.933 22939 0.042 1.19 0.943 1551 0.037 1.17 0.943 1968 CX rs5914778 56774956 G 0.804 22928 0.002 1.18 0.828 1550 0.0032 1.15 0.825 1966 CX rs2031751 67165559 C 0.941 22937 0.08 1.17 0.949 1550 0.051 1.17 0.949 1967 CX rs1576059 67171306 T 0.941 22937 0.076 1.17 0.949 1551 0.056 1.17 0.949 1968 CX rs7050085 67278825 G 0.908 22941 0.015 1.19 0.922 1550 0.0059 1.20 0.922 1967 CX rs2341629 70367614 C 0.470 22923 0.093 1.07 0.487 1550 0.16 1.05 0.483 1967 CX rs2213468 86099449 G 0.668 22877 0.047 1.09 0.687 1541 0.15 1.06 0.680 1958 CX rs6615536 92662125 G 0.988 22935 0.0094 1.77 0.993 1551 0.00098 1.97 0.994 1968 CX rs2227165 92880063 C 0.899 8732 0.00000074 1.56 0.933 1121 0.00013 1.37 0.924 1314 CX rs3788769 109423718 C 0.441 22401 0.0016 1.14 0.473 1534 0.0018 1.12 0.470 1944 CX rs2526763 116328390 G 0.365 22923 0.006 1.12 0.392 1549 0.0083 1.10 0.388 1965 CX rs1948488 139835516 A 0.222 22466 0.043 1.10 0.239 1527 0.02 1.11 0.240 1937 CX rs11094472 144273211 G 0.787 22928 0.00017 1.21 0.818 1545 0.004 1.14 0.808 1962

TABLE 4 Results of replication analysis in several populations. A total of 100 markers from the genome-wide scan shown in Table 3 were selected for replication. The table shows results of replication in cohorts from Atlanta and Durham (A - MI; B - CAD), Durham and Italy (C - MI; D - CAD), John Hopkins, WTCCC and in combined replication samples (E - MI; F - CAD), and results for the Icelandic discovery cohort and combined analysis for all the cohorts (G - MI; H - CAD). The number of controls/cases is shown for each analysis. Table 4A - MI Atlanta (1273/646) Philadelphia (497/570) Chr SNP Pos_B36 Allele nc/na Ctr. fr Aff. fr OR P nc/na Ctr. fr Aff. fr OR P C06 rs11751605 160883220 C 1273/643 0.155 0.163 1.06 0.53 497/566 0.131 0.135 1.04 0.77 C10 rs2243547 91000459 G C10 rs1412444 90992907 A  581/367 0.333 0.356 1.10 0.31 496/570 0.326 0.353 1.13 0.19 C01 rs12134779 63168930 T 1260/578 0.285 0.289 1.02 0.78 497/567 0.270 0.271 1.01 0.95 C11 rs2163612 82856844 G  513/367 0.496 0.499 1.01 0.92 465/522 0.488 0.513 1.11 0.26 C05 rs254850 158599309 T C17 rs9902941 17674485 C 1210/591 0.352 0.372 1.09 0.25 474/542 0.393 0.423 1.13 0.17 C20 rs6076623 4084671 T 1246/621 0.303 0.335 1.16 0.051 494/562 0.283 0.276 0.96 0.7 C05 rs4921437 158623529 T C05 rs832540 56234959 C C19 rs12459084 17031885 T C07 rs1029396 116812056 G  572/363 0.082 0.094 1.15 0.39 491/562 0.074 0.070 0.94 0.72 C17 rs6502622 17775416 G 1227/593 0.366 0.401 1.16 0.042 475/540 0.409 0.433 1.10 0.28 C17 rs854787 17975744 C  507/360 0.399 0.475 1.36 0.0017 475/542 0.433 0.458 1.11 0.24 C14 rs7158073 99211442 T  575/362 0.408 0.419 1.04 0.65 480/549 0.426 0.448 1.09 0.31 C10 rs2243548 91000293 A C17 rs4925119 17683629 A 1207/646 0.349 0.372 1.11 0.16 470/537 0.397 0.419 1.10 0.31 C17 rs3183702 17688014 T  539/362 0.337 0.391 1.26 0.019 469/531 0.393 0.427 1.15 0.13 C17 rs854813 17944570 C  539/364 0.388 0.449 1.29 0.0094 462/520 0.429 0.468 1.17 0.077 C05 rs953861 158705160 G C07 rs12534186 117079572 T C12 rs2417821 20081535 T C20 rs1741318 4105600 A C06 rs2074464 29516507 T  576/365 0.442 0.484 1.18 0.077 491/554 0.486 0.464 0.92 0.32 C07 rs324594 136305863 C C05 rs270654 158497687 G C15 rs4779984 30302218 G C05 rs7709212 158696755 T C05 rs10045431 158747111 A C17 rs2955355 17889200 C  534/360 0.291 0.360 1.37 0.0024 476/544 0.352 0.362 1.05 0.63 C11 rs7944761 1361414 T C05 rs4704400 76586766 T 416/485 0.460 0.468 1.03 0.74 C17 rs4925114 17651995 A  521/361 0.343 0.378 1.17 0.13 473/539 0.403 0.400 0.99 0.89 C05 rs1433048 158688423 G C05 rs7447732 158461713 C 1225/544 0.315 0.312 0.99 0.85 497/567 0.272 0.311 1.21 0.045 C02 rs2244871 128115310 C  500/349 0.431 0.430 1.00 0.96 456/509 0.459 0.449 0.96 0.64 C01 rs2946534 18647370 T C04 rs7661204 45728C07 T C05 rs6556861 94554256 G C06 rs7753765 71732495 A  532/366 0.172 0.182 1.07 0.6 479/533 0.175 0.174 0.99 0.96 C05 rs870347 6898035 T C10 rs12269612 15475877 T C15 rs2110209 24946433 A C02 rs12329252 212093968 T 1250/554 0.681 0.680 0.99 0.94 492/569 0.682 0.683 1.00 0.97 C14 rs8003722 68388015 A 1029/472 0.147 0.151 1.04 0.73 C21 rs2828495 24038081 A C05 rs270661 158492732 A C08 rs334198 18933089 C  542/367 0.918 0.914 0.95 0.78 475/543 0.900 0.912 1.15 0.37 C01 rs2476601 114179091 A 1188/280 0.093 0.113 1.23 0.18 462/540 0.093 0.096 1.04 0.81 C13 rs4769613 28036609 T C08 rs3102526 96858538 G C08 rs3134517 96859237 G C01 rs3748744 19828833 G C04 rs4282162 21426819 T C16 rs8050136 52373776 A 488/561 0.408 0.415 1.03 0.73 C16 rs3751812 52375961 T 490/567 0.397 0.405 1.03 0.71 C17 rs854793 17971249 A  539/369 0.213 0.255 1.26 0.04 454/505 0.246 0.260 1.08 0.46 C10 rs4880711 5217871 C C12 rs12304836 124654446 C 1217/588 0.152 0.151 0.99 0.88 472/532 0.145 0.173 1.23 0.089 C05 rs38055 52596401 T 1259/556 0.311 0.341 1.15 0.072 491/565 0.305 0.340 1.17 0.092 C09 rs2297538 138684489 G 404/454 0.786 0.739 0.77 0.023 C16 rs1870843 81316815 T C06 rs6905466 19958854 T C12 rs11045689 21092930 G 1196/419 0.345 0.344 0.99 0.95 492/556 0.362 0.346 0.93 0.46 C13 rs1887263 22381716 A C18 rs4271662 26051291 C 1216/551 0.598 0.613 1.07 0.38 487/553 0.611 0.613 1.01 0.92 C18 rs1365254 70238283 T C06 rs3016536 162157939 G C12 rs3742049 119438873 C  584/364 0.901 0.905 1.05 0.75 C03 rs9874646 62437858 T 1193/414 0.684 0.687 1.01 0.86 492/559 0.648 0.678 1.14 0.15 C14 rs2281519 93846385 T C02 rs6747236 35901725 T  975/276 0.756 0.777 1.12 0.31 460/523 0.771 0.750 0.90 0.3 C04 rs6534683 129601758 T C01 rs2991515 57656898 T 1136/387 0.453 0.463 1.04 0.66 427/497 0.474 0.466 0.97 0.72 C04 rs4697653 10337857 G 447/520 0.534 0.533 1.00 0.97 C06 rs9380681 37638433 C C10 rs11199158 85297471 G C13 rs1375719 102208783 C  584/362 0.529 0.514 0.94 0.52 C08 rs3931282 129179963 T  587/362 0.532 0.562 1.13 0.21 C14 rs17776453 100774793 G C01 rs12724604 20948045 A C05 rs950195 97466690 G C05 rs728676 118087433 T 1012/464 0.465 0.498 1.14 0.1 C06 rs7739802 162154323 T C10 rs7086224 30857283 A C01 rs4845552 151746622 G C08 rs10504537 73402234 A C02 rs1395930 123468570 T 1216/559 0.531 0.484 0.83 0.0087 489/555 0.516 0.529 1.05 0.57 C02 rs3943703 127613790 C C10 rs2279434 45275070 T  513/362 0.084 0.070 0.83 0.3 472/532 0.097 0.081 0.81 0.19 C10 rs11198993 85244450 A C10 rs7921473 85156395 G C12 rs1465026 65789635 G C12 rs1568383 88017285 T  537/370 0.127 0.105 0.81 0.17 467/528 0.123 0.116 0.94 0.65 C08 rs4732849 28249765 T 1160/411 0.316 0.330 1.06 0.48 486/554 0.315 0.312 0.99 0.9 C08 rs7006687 18277862 T C02 rs921083 176453128 G 493/563 0.813 0.804 0.94 0.57 C02 rs6709904 43933828 A C14 rs1957860 53499105 T 1188/419 0.476 0.486 1.04 0.62 492/565 0.497 0.471 0.90 0.23 C14 rs4444235 53480669 T 1160/404 0.534 0.524 0.96 0.62 489/551 0.535 0.521 0.95 0.53 Table 4B - CAD Pos Build Atlanta (1273/772) Philadelphia (497/700) Chr SNP 36 Allele nc/na Ctr. fr Aff. fr OR P nc/na Ctr. fr Aff. fr OR P C06 rs11751605 160883220 C 1273/772 0.155 0.163 1.07 0.47 497/693 0.131 0.139 1.08 0.55 C20 rs6076623 4084671 T 1246/748 0.303 0.326 1.11 0.14 494/689 0.283 0.275 0.96 0.65 C10 rs1412444 90992907 A  581/475 0.333 0.348 1.07 0.46 496/700 0.326 0.353 1.13 0.17 C11 rs2163612 82856844 G  513/466 0.496 0.510 1.06 0.55 465/539 0.488 0.512 1.10 0.29 C07 rs1029396 116812056 G  572/471 0.082 0.086 1.05 0.75 491/692 0.074 0.072 0.97 0.85 C10 rs2243547 91000459 G C07 rs12534186 117079572 T C01 rs12134779 63168930 T 1260/706 0.285 0.290 1.03 0.73 497/695 0.270 0.260 0.95 0.59 C14 rs7158073 99211442 T  575/469 0.408 0.414 1.02 0.79 480/673 0.426 0.442 1.07 0.44 C05 rs254850 158599309 T C12 rs2417821 20081535 T C04 rs7661204 45728007 T C05 rs4921437 158623529 T C05 rs832540 56234959 C C07 rs324594 136305863 C C20 rs1741318 4105600 A C17 rs9902941 17674485 C 1210/719 0.352 0.373 1.09 0.21 474/557 0.393 0.419 1.11 0.24 C05 rs7709212 158696755 T C01 rs2946534 18647370 T C05 rs6556861 94554256 G C16 rs8050136 52373776 A 488/685 0.408 0.420 1.05 0.54 C16 rs3751812 52375961 T 490/692 0.397 0.410 1.05 0.53 C13 rs4769613 28036609 T C10 rs2243548 91000293 A C19 rs12459084 17031885 T C06 rs2074464 29516507 T  576/474 0.442 0.465 1.10 0.28 491/677 0.486 0.470 0.94 0.44 C02 rs2244871 128115310 C  500/444 0.431 0.422 0.96 0.7 456/525 0.459 0.451 0.97 0.72 C05 rs270654 158497687 G C17 rs854787 17975744 C  507/459 0.399 0.459 1.27 0.0086 475/560 0.433 0.454 1.09 0.34 C11 rs7944761 1361414 T C15 rs4779984 30302218 G C17 rs6502622 17775416 G 1227/719 0.366 0.403 1.17 0.021 475/558 0.409 0.429 1.08 0.36 C17 rs3183702 17688014 T  539/465 0.337 0.387 1.24 0.019 469/548 0.393 0.422 1.12 0.2 C05 rs1433048 158688423 G C17 rs4925119 17683629 A 1207/770 0.349 0.373 1.11 0.13 470/555 0.397 0.414 1.08 0.42 C01 rs2476601 114179091 A 1188/323 0.093 0.121 1.33 0.044 462/666 0.093 0.098 1.05 0.72 C05 rs870347 6898035 T C08 rs334198 18933089 C  542/472 0.918 0.908 0.88 0.42 475/561 0.900 0.912 1.15 0.36 C17 rs854813 17944570 C  539/467 0.388 0.442 1.25 0.013 462/538 0.429 0.465 1.16 0.11 C06 rs7753765 71732495 A  532/468 0.172 0.174 1.02 0.9 479/551 0.175 0.172 0.97 0.82 C17 rs4925114 17651995 A  521/461 0.343 0.379 1.17 0.098 473/555 0.403 0.395 0.97 0.74 C05 rs270661 158492732 A C05 rs953861 158705160 G C05 rs10045431 158747111 A C14 rs8003722 68388015 A 1029/530 0.147 0.151 1.03 0.75 C09 rs2297538 138684489 G 404/555 0.786 0.749 0.81 0.057 C02 rs12329252 212093968 T 1250/681 0.681 0.675 0.97 0.7 492/696 0.682 0.685 1.02 0.86 C01 rs3748744 19828833 G C05 rs4704400 76586766 T 416/576 0.460 0.462 1.01 0.95 C08 rs3102526 96858538 G C15 rs2110209 24946433 A C16 rs1870843 81316815 T C08 rs3134517 96859237 G C21 rs2828495 24038081 A C04 rs4282162 21426819 T C17 rs2955355 17889200 C  534/463 0.291 0.351 1.32 0.0043 476/562 0.352 0.359 1.03 0.72 C12 rs11045689 21092930 G 1196/462 0.345 0.345 1.00 0.99 492/680 0.362 0.347 0.94 0.46 C05 rs7447732 158461713 C 1225/669 0.315 0.299 0.93 0.32 497/691 0.272 0.310 1.20 0.044 C18 rs1365254 70238283 T C13 rs1887263 22381716 A C12 rs12304836 124654446 C 1217/712 0.152 0.151 0.99 0.9 472/550 0.145 0.170 1.21 0.12 C05 rs38055 52596401 T 1259/680 0.311 0.337 1.13 0.096 491/690 0.305 0.341 1.17 0.073 C04 rs4697653 10337857 G 447/619 0.534 0.537 1.01 0.87 C05 rs728676 118087433 T 1012/522 0.465 0.496 1.13 0.11 C06 rs6905466 19958854 T C10 rs11199158 85297471 G C01 rs4845552 151746622 G C02 rs1395930 123468570 T 1216/686 0.531 0.483 0.83 0.0044 489/681 0.516 0.524 1.03 0.71 C04 rs6534683 129601758 T C02 rs6747236 35901725 T  975/312 0.756 0.782 1.16 0.19 460/640 0.771 0.761 0.95 0.6 C06 rs3016536 162157939 G C10 rs12269612 15475877 T C17 rs854793 17971249 A  539/475 0.213 0.252 1.24 0.042 454/522 0.246 0.259 1.07 0.51 C12 rs3742049 119438873 C  584/470 0.901 0.904 1.04 0.78 C01 rs2991515 57656898 T 1136/430 0.453 0.462 1.03 0.68 427/621 0.474 0.461 0.95 0.56 C18 rs4271662 26051291 C 1216/676 0.598 0.611 1.06 0.43 487/676 0.611 0.620 1.04 0.66 C06 rs7739802 162154323 T C08 rs10504537 73402234 A C14 rs17776453 100774793 G C10 rs7086224 30857283 A C01 rs12724604 20948045 A C03 rs9874646 62437858 T 1193/457 0.684 0.690 1.03 0.72 492/683 0.648 0.679 1.15 0.13 C05 rs950195 97466690 G C14 rs2281519 93846385 T C10 rs4880711 5217871 C C08 rs3931282 129179963 T  587/469 0.532 0.560 1.12 0.21 C10 rs11198993 85244450 A C12 rs1568383 88017285 T  537/472 0.127 0.105 0.81 0.13 467/546 0.123 0.116 0.94 0.64 C06 rs9380681 37638433 C C02 rs6709904 43933828 A 959/51 0.903 0.912 1.12 0.76 C10 rs2279434 45275070 T  513/462 0.084 0.076 0.90 0.51 472/550 0.097 0.078 0.79 0.12 C13 rs1375719 102208783 C  584/469 0.529 0.499 0.89 0.17 C10 rs7921473 85156395 G C14 rs1957860 53499105 T 1188/462 0.476 0.483 1.03 0.71 492/691 0.497 0.475 0.91 0.29 C02 rs3943703 127613790 C C08 rs7006687 18277862 T C12 rs1465026 65789635 G C14 rs4444235 53480669 T 1160/445 0.534 0.527 0.97 0.74 489/673 0.535 0.516 0.93 0.36 C02 rs921083 176453128 G 493/689 0.813 0.810 0.98 0.83 C08 rs4732849 28249765 T 1160/454 0.316 0.326 1.05 0.6 486/678 0.315 0.316 1.00 0.97 Table 4C - MI Durham (737/1199) Italy (1076/657) Chr SNP Pos_B36 Allele nc/na Ctr. fr Aff. fr OR P nc/na Ctr. fr Aff. fr OR P C06 rs11751605 160883220 C 731/1187 0.158 0.174 1.12 0.21 1075/656 0.083 0.100 1.22 0.099 C10 rs2243547 91000459 G C10 rs1412444 90992907 A 730/1190 0.344 0.356 1.05 0.45 1068/646 0.309 0.328 1.09 0.25 C01 rs12134779 63168930 T 731/1191 0.282 0.309 1.14 0.078 1055/646 0.248 0.266 1.10 0.25 C11 rs2163612 62856844 G 732/1182 0.484 0.491 1.03 0.67 C05 rs254850 158599309 T C17 rs9902941 17674485 C 736/1150 0.355 0.378 1.10 0.15 C20 rs6076623 4084671 T 737/1195 0.307 0.323 1.08 0.28 1062/649 0.222 0.213 0.95 0.57 C05 rs4921437 158623529 T 725/1194 0.197 0.194 0.98 0.8 1045/639 0.171 0.174 1.02 0.81 C05 rs832540 56234959 C 711/1175 0.370 0.385 1.06 0.36 1052/642 0.372 0.363 0.96 0.59 C19 rs12459084 17031885 T 732/1196 0.413 0.409 0.98 0.82 C07 rs1029396 116812056 G 735/1197 0.083 0.102 1.26 0.045 1076/657 0.062 0.053 0.84 0.25 C17 rs6502622 17775416 G 734/1150 0.377 0.400 1.10 0.17 1048/639 0.456 0.450 0.98 0.75 C17 rs854787 17975744 C 732/1180 0.413 0.438 1.11 0.13 1017/611 0.501 0.489 0.95 0.52 C14 rs7158073 99211442 T 719/1159 0.429 0.461 1.14 0.058  490/270 0.458 0.407 0.81 0.056 C10 rs2243548 91000293 A C17 rs4925119 17683629 A 729/1173 0.350 0.374 1.11 0.13 1026/640 0.437 0.430 0.97 0.67 C17 rs3183702 17688014 T 572/926  0.355 0.369 1.06 0.44 1059/641 0.435 0.422 0.95 0.46 C17 rs854813 17944570 C 209/412  0.392 0.417 1.11 0.39 1057/646 0.502 0.469 0.88 0.059 C05 rs953861 158705160 G C07 rs12534186 117079572 T C12 rs2417821 20081535 T 725/1186 0.720 0.721 1.01 0.93 1042/641 0.668 0.670 1.01 0.92 C20 rs1741318 4105600 A C06 rs2074464 29516507 T 728/1184 0.451 0.466 1.06 0.37 1034/634 0.462 0.452 0.96 0.58 C07 rs324594 136305863 C C05 rs270654 158497687 G C15 rs4779984 30302218 G C05 rs7709212 158696755 T C05 rs10045431 158747111 A C17 rs2955355 17889200 C 212/413  0.302 0.337 1.17 0.21 1052/614 0.402 0.374 0.89 0.11 C11 rs7944761 1361414 T C05 rs4704400 76586766 T C17 rs4925114 17651995 A 211/413  0.353 0.389 1.16 0.22 C05 rs1433048 158688423 G C05 rs7447732 158461713 C 732/1198 0.328 0.314 0.94 0.37 1067/643 0.305 0.285 0.91 0.23 C02 rs2244871 128115310 C 563/924  0.388 0.439 1.24 0.0059 C01 rs2946534 18647370 T C04 rs7661204 45728007 T 720/1183 0.411 0.435 1.10 0.14 C05 rs6556861 94554256 G 719/1169 0.631 0.615 0.93 0.33 1056/637 0.652 0.633 0.92 0.27 C06 rs7753765 71732495 A C05 rs870347 6898035 T C10 rs12269612 15475877 T 734/1196 0.382 0.361 0.91 0.19 1055/634 0.382 0.363 0.92 0.26 C15 rs2110209 24946433 A 737/1191 0.035 0.032 0.93 0.7 C02 rs12329252 212093968 T 737/1197 0.659 0.665 1.03 0.69 1047/642 0.713 0.694 0.91 0.23 C14 rs8003722 68388015 A 735/1186 0.144 0.136 0.94 0.48 C21 rs2828495 24038081 A C05 rs270661 158492732 A 736/1196 0.209 0.189 0.89 0.15 1066/652 0.194 0.173 0.87 0.12 C08 rs334198 18933089 C C01 rs2476601 114179091 A 572/921  0.087 0.097 1.14 0.33 1049/647 0.062 0.070 1.12 0.42 C13 rs4769613 28036609 T 733/1190 0.458 0.463 1.02 0.77 1052/632 0.498 0.487 0.96 0.53 C08 rs3102526 96858538 G C08 rs3134517 96859237 G C01 rs3748744 19828833 G C04 rs4282162 21426819 T 732/1198 0.488 0.488 1.00 0.99 C16 rs8050136 52373776 A 1064/635 0.414 0.425 1.05 0.52 C16 rs3751812 52375961 T 1070/651 0.412 0.420 1.04 0.63 C17 rs854793 17971249 A 213/393  0.202 0.224 1.14 0.37 1031/649 0.268 0.240 0.87 0.077 C10 rs4880711 5217871 C C12 rs12304836 124654446 C 729/1172 0.147 0.145 0.99 0.91 C05 rs380555 2596401 T 729/1194 0.306 0.311 1.02 0.75 1054/641 0.316 0.306 0.95 0.54 C09 rs2297538 138684489 G 736/1193 0.798 0.795 0.98 0.79  712/231 0.754 0.755 1.01 0.96 C16 rs18708438 1316815 T C06 rs6905466 19958854 T C12 rs11045689 21092930 G 734/1195 0.328 0.365 1.18 0.019 C13 rs1887263 22381716 A C18 rs4271662 26051291 C 736/1194 0.596 0.601 1.02 0.76 1045/621 0.644 0.634 0.96 0.55 C18 rs1365254 70238283 T C06 rs3016536 162157939 G C12 rs3742049 119438873 C 120/254  0.896 0.884 0.88 0.63 C03 rs9874646 62437858 T 735/1199 0.686 0.681 0.98 0.74 C14 rs2281519 93846385 T C02 rs6747236 35901725 T 432/1102 0.760 0.774 1.08 0.44 C04 rs6534683 129601758 T C01 rs2991515 57656898 T C04 rs4697653 10337857 G 723/1187 0.558 0.540 0.93 0.27 1019/624 0.546 0.559 1.06 0.44 C06 rs9380681 37638433 C C10 rs11199158 85297471 G 734/1195 0.636 0.638 1.01 0.89 1049/641 0.653 0.651 0.99 0.91 C13 rs1375719 102208783 C 116/250  0.504 0.464 0.85 0.31 C08 rs3931282 129179963 T 732/1182 0.524 0.542 1.08 0.27 C14 rs17776453 100774793 G C01 rs12724604 20948045 A C05 rs950195 97466690 G 727/1193 0.646 0.633 0.94 0.39 1036/637 0.647 0.617 0.88 0.083 C05 rs728676 118087433 T 718/1152 0.493 0.486 0.97 0.66 C06 rs7739802 162154323 T C10 rs7086224 30857283 A C01 rs4845552 151746622 G 736/1197 0.140 0.154 1.12 0.24 1060/647 0.153 0.123 0.78 0.014 C08 rs10504537 73402234 A C02 rs1395930 123468570 T 737/1188 0.507 0.508 1.00 0.97 1037/638 0.548 0.571 1.10 0.18 C02 rs3943703 127613790 C C10 rs2279434 45275070 T C10 rs11198993 85244450 A 732/1192 0.774 0.759 0.92 0.3 1048/641 0.776 0.786 1.06 0.49 C10 rs7921473 85156395 G 733/1177 0.840 0.828 0.91 0.3 1064/644 0.823 0.816 0.95 0.61 C12 rs1465026 65789635 G 731/1189 0.837 0.821 0.90 0.21 1061/654 0.842 0.847 1.04 0.67 C12 rs1568383 88017285 T C08 rs4732849 28249765 T 724/1188 0.330 0.314 0.93 0.3 C08 rs7006687 18277862 T 730/1196 0.567 0.549 0.93 0.27 1056/641 0.561 0.512 0.82 0.0059 C02 rs921083 176453128 G 734/1199 0.809 0.817 1.06 0.5 1057/636 0.828 0.831 1.02 0.81 C02 rs6709904 43933828 A 682/1110 0.891 0.885 0.94 0.58 C14 rs1957860 53499105 T 737/1198 0.455 0.483 1.12 0.082 C14 rs4444235 53480669 T 733/1186 0.548 0.527 0.92 0.22 Table 4D - CAD Pos Build Durham (737/1199) Italy (1076/1122) Chr SNP 36 Allele nc/na Ctr. fr Aff. fr OR P nc/na Ctr. fr Aff. fr OR P C06 rs11751605 160883220 C 731/1187 0.158 0.174 1.12 0.21 1075/1122 0.083 0.099 1.21 0.071 C20 rs6076623 4084671 T 737/1195 0.307 0.323 1.08 0.28 1062/1105 0.222 0.222 1.00 1 C10 rs1412444 90992907 A 730/1190 0.344 0.356 1.05 0.45 1068/1105 0.309 0.330 1.10 0.15 C11 rs2163612 82856844 G 732/1182 0.484 0.491 1.03 0.67 C07 rs1029396 116812056 G 735/1197 0.083 0.102 1.26 0.045 1076/1121 0.062 0.052 0.83 0.15 C10 rs2243547 91000459 G C07 rs12534186 117079572 T C01 rs12134779 63168930 T 731/1191 0.282 0.309 1.14 0.078 1055/1106 0.248 0.270 1.12 0.099 C14 rs7158073 99211442 T 719/1159 0.429 0.461 1.14 0.058 490/449 0.458 0.450 0.97 0.72 C05 rs254850 158599309 T C12 rs2417821 20081535 T 725/1186 0.720 0.721 1.01 0.93 1042/1100 0.668 0.670 1.01 0.91 C04 rs7661204 45728007 T 720/1183 0.411 0.435 1.10 0.14 C05 rs4921437 158623529 T 725/1194 0.197 0.194 0.98 0.8 1045/1092 0.171 0.178 1.05 0.56 C05 rs832540 56234959 C 711/1175 0.370 0.385 1.06 0.36 1052/1102 0.372 0.365 0.97 0.64 C07 rs324594 136305863 C C20 rs1741318 4105600 A C17 rs9902941 17674485 C 736/1150 0.355 0.378 1.10 0.15 C05 rs7709212 158696755 T C01 rs2946534 18647370 T C05 rs6556861 94554256 G 719/1169 0.631 0.615 0.93 0.33 1056/1099 0.652 0.658 1.03 0.66 C16 rs8050136 52373776 A 1064/1091 0.414 0.425 1.05 0.47 C16 rs3751812 52375961 T 1070/1114 0.412 0.420 1.03 0.59 C13 rs4769613 28036609 T 733/1190 0.458 0.463 1.02 0.77 1052/1090 0.498 0.488 0.96 0.51 C10 rs2243548 91000293 A C19 rs12459084 17031885 T 732/1196 0.413 0.409 0.98 0.82 C06 rs2074464 29516507 T 728/1184 0.451 0.466 1.06 0.37 1034/1082 0.462 0.448 0.94 0.36 C02 rs2244871 128115310 C 563/924  0.388 0.439 1.24 0.0059 C05 rs270654 158497687 G C17 rs854787 17975744 C 732/1180 0.413 0.438 1.11 0.13 1017/1043 0.501 0.490 0.96 0.48 C11 rs7944761 1361414 T C15 rs4779984 30302218 G C17 rs6502622 17775416 G 734/1150 0.377 0.400 1.10 0.17 1048/1098 0.456 0.443 0.95 0.41 C17 rs3183702 17688014 T 572/926  0.355 0.369 1.06 0.44 1059/1099 0.435 0.421 0.95 0.37 C05 rs1433048 158688423 G C17 rs4925119 17683629 A 729/1173 0.350 0.374 1.11 0.13 1026/1082 0.437 0.423 0.95 0.36 C01 rs2476601 114179091 A 572/921  0.087 0.097 1.14 0.33 1049/1107 0.062 0.067 1.08 0.52 C05 rs870347 6898035 T C08 rs334198 18933089 C C17 rs854813 17944570 C 209/412  0.392 0.417 1.11 0.39 1057/1102 0.502 0.471 0.88 0.036 C06 rs7753765 71732495 A C17 rs4925114 17651995 A 211/413  0.353 0.389 1.16 0.22 C05 rs270661 158492732 A 736/1196 0.209 0.189 0.89 0.15 1066/1112 0.194 0.188 0.96 0.63 C05 rs953861 158705160 G C05 rs10045431 158747111 A C14 rs8003722 68388015 A 735/1186 0.144 0.136 0.94 0.48 C09 rs2297538 138684489 G 736/1193 0.798 0.795 0.98 0.79 712/386 0.754 0.750 0.98 0.83 C02 rs12329252 212093968 T 737/1197 0.659 0.665 1.03 0.69 1047/1095 0.713 0.688 0.88 0.065 C01 rs3748744 19828833 G C05 rs4704400 76586766 T C08 rs3102526 96858538 G C15 rs2110209 24946433 A 737/1191 0.035 0.032 0.93 0.7 C16 rs1870843 81316815 T C08 rs3134517 96859237 G C21 rs2828495 24038081 A C04 rs4282162 21426819 T 732/1198 0.488 0.488 1.00 0.99 C17 rs2955355 17889200 C 212/413  0.302 0.337 1.17 0.21 1052/1055 0.402 0.369 0.87 0.028 C12 rs11045689 21092930 G 734/1195 0.328 0.365 1.18 0.019 C05 rs7447732 158461713 C 732/1198 0.328 0.314 0.94 0.37 1067/1100 0.305 0.282 0.90 0.11 C18 rs1365254 70238283 T C13 rs1887263 22381716 A C12 rs12304836 124654446 C 729/1172 0.147 0.145 0.99 0.91 C05 rs38055 52596401 T 729/1194 0.306 0.311 1.02 0.75 1054/1102 0.316 0.305 0.95 0.45 C04 rs4697653 10337857 G 723/1187 0.558 0.540 0.93 0.27 1019/1076 0.546 0.571 1.11 0.097 C05 rs728676 118087433 T 718/1152 0.493 0.486 0.97 0.66 C06 rs6905466 19958854 T C10 rs11199158 85297471 G 734/1195 0.636 0.638 1.01 0.89 1049/1093 0.653 0.655 1.01 0.86 C01 rs4845552 151746622 G 736/1197 0.140 0.154 1.12 0.24 1060/1105 0.153 0.134 0.86 0.076 C02 rs1395930 123468570 T 737/1188 0.507 0.508 1.00 0.97 1037/1085 0.548 0.565 1.07 0.26 C04 rs6534683 129601758 T C02 rs6747236 35901725 T 432/1102 0.760 0.774 1.08 0.44 C06 rs3016536 162157939 G C10 rs12269612 15475877 T 734/1196 0.382 0.361 0.91 0.19 1055/1088 0.382 0.353 0.88 0.049 C17 rs854793 17971249 A 213/393  0.202 0.224 1.14 0.37 1031/1102 0.268 0.245 0.89 0.083 C12 rs3742049 119438873 C 120/254  0.896 0.884 0.88 0.63 C01 rs2991515 57656898 T C18 rs4271662 26051291 C 736/1194 0.596 0.601 1.02 0.76 1045/1075 0.644 0.633 0.95 0.44 C06 rs7739802 162154323 T C08 rs10504537 73402234 A C14 rs17776453 100774793 G C10 rs7086224 30857283 A C01 rs12724604 20948045 A C03 rs9874646 62437858 T 735/1199 0.686 0.681 0.98 0.74 C05 rs950195 97466690 G 727/1193 0.646 0.633 0.94 0.39 1036/1086 0.647 0.622 0.90 0.095 C14 rs2281519 93846385 T C10 rs4880711 5217871 C C08 rs3931282 129179963 T 732/1182 0.524 0.542 1.08 0.27 C10 rs11198993 85244450 A 732/1192 0.774 0.759 0.92 0.3 1048/1096 0.776 0.778 1.01 0.87 C12 rs1568383 88017285 T C06 rs9380681 37638433 C C02 rs6709904 43933828 A 682/1110 0.891 0.885 0.94 0.58 C10 rs2279434 45275070 T C13 rs1375719 102208783 C 116/250  0.504 0.464 0.85 0.31 C10 rs7921473 85156395 G 733/1177 0.840 0.828 0.91 0.3 1064/1104 0.823 0.819 0.97 0.73 C14 rs1957860 53499105 T 737/1198 0.455 0.483 1.12 0.082 C02 rs3943703 127613790 C C08 rs7006687 18277862 T 730/1196 0.567 0.549 0.93 0.27 1056/1094 0.561 0.521 0.85 0.0077 C12 rs1465026 65789635 G 731/1189 0.837 0.821 0.90 0.21 1061/1118 0.842 0.842 1.00 0.97 C14 rs4444235 53480669 T 733/1186 0.548 0.527 0.92 0.22 C02 rs921083 176453128 G 734/1199 0.809 0.817 1.06 0.5 1057/1096 0.828 0.828 1.00 0.99 C08 rs4732849 28249765 T 724/1188 0.330 0.314 0.93 0.3 Table 4E - MI Pos in Hopkins (1567/184) Chr SNP Build 36 Allele nc/na Ctr. fr Aff. fr OR P C06 rs11751605 160883220 C 1565/184 0.155 0.179 1.19 0.23 C10 rs2243547 91000459 G 1539/184 0.284 0.323 1.21 0.12 C10 rs1412444 90992907 A 1565/183 0.321 0.344 1.11 0.38 C01 rs12134779 63168930 T 1567/183 0.265 0.281 1.08 0.52 C11 rs2163612 82856844 G 1566/182 0.497 0.489 0.97 0.78 C05 rs254850 158599309 T 1567/184 0.195 0.190 0.97 0.83 C17 rs9902941 17674485 C 1567/183 0.367 0.350 0.93 0.51 C20 rs6076623 4084671 T 1567/183 0.296 0.325 1.15 0.25 C05 rs4921437 158623529 T 1566/183 0.184 0.189 1.03 0.84 C05 rs832540 56234959 C 1567/184 0.361 0.397 1.16 0.18 C19 rs12459084 17031885 T 1512/182 0.415 0.434 1.08 0.48 C07 rs1029396 116812056 G 1566/183 0.080 0.115 1.50 0.027 C17 rs6502622 17775416 G 1563/184 0.401 0.386 0.94 0.59 C17 rs854787 17975744 C 1552/181 0.428 0.406 0.92 0.43 C14 rs7158073 99211442 T 1509/180 0.431 0.428 0.99 0.9 C10 rs2243548 91000293 A 1566/183 0.504 0.544 1.17 0.15 C17 rs4925119 17683629 A 1542/181 0.361 0.340 0.91 0.43 C17 rs3183702 17688014 T 1561/183 0.365 0.344 0.92 0.44 C17 rs854813 17944570 C 1551/180 0.409 0.381 0.89 0.3 C05 rs953861 158705160 G 1565/184 0.168 0.168 1.00 1 C07 rs12534186 117079572 T 1567/184 0.095 0.125 1.36 0.077 C12 rs2417821 20081535 T 1566/184 0.728 0.723 0.97 0.82 C20 rs1741318 4105600 A 1566/183 0.377 0.383 1.02 0.83 C06 rs2074464 29516507 T 1562/183 0.447 0.426 0.92 0.46 C07 rs324594 136305863 C 1567/183 0.269 0.240 0.86 0.23 C05 rs270654 158497687 G 1567/183 0.108 0.096 0.88 0.48 C15 rs4779984 30302218 G 1562/183 0.125 0.134 1.08 0.64 C05 rs7709212 158696755 T 1567/183 0.674 0.699 1.12 0.33 C05 rs10045431 158747111 A 1567/184 0.289 0.299 1.05 0.7 C17 rs2955355 17889200 C 1565/183 0.318 0.306 0.95 0.65 C11 rs7944761 1361414 T 1567/184 0.563 0.571 1.03 0.79 C05 rs4704400 76586766 T 1563/183 0.485 0.503 1.07 0.52 C17 rs4925114 17651995 A 1561/183 0.372 0.344 0.89 0.3 C05 rs1433048 158688423 G 1565/183 0.184 0.172 0.92 0.56 C05 rs7447732 158461713 C 1566/184 0.321 0.323 1.01 0.92 C02 rs2244871 128115310 C 1556/182 0.426 0.396 0.88 0.26 C01 rs2946534 18647370 T 1564/183 0.548 0.552 1.02 0.88 C04 rs7661204 45728007 T 1567/183 0.410 0.385 0.90 0.36 C05 rs6556861 94554256 G 1567/183 0.623 0.612 0.95 0.68 C06 rs7753765 71732495 A 1567/184 0.170 0.188 1.13 0.4 C05 rs870347 6898035 T 1566/184 0.940 0.946 1.11 0.66 C10 rs12269612 15475877 T 1567/184 0.376 0.399 1.10 0.38 C15 rs2110209 24946433 A 1567/184 0.031 0.024 0.78 0.46 C02 rs12329252 212093968 T 1567/183 0.657 0.678 1.10 0.44 C14 rs8003722 68388015 A 1566/183 0.138 0.139 1.01 0.93 C21 rs2828495 24038081 A 1566/183 0.233 0.230 0.98 0.89 C05 rs270661 158492732 A 1567/184 0.194 0.171 0.86 0.29 C08 rs334198 18933089 C 1566/184 0.922 0.924 1.02 0.92 C01 rs2476601 114179091 A 1566/183 0.091 0.096 1.06 0.77 C13 rs4769613 28036609 T 1567/183 0.469 0.514 1.20 0.11 C08 rs3102526 96858538 G 1565/183 0.620 0.658 1.18 0.15 C08 rs3134517 96859237 G 1567/184 0.620 0.658 1.18 0.15 C01 rs3748744 19828833 G 1561/182 0.896 0.912 1.21 0.32 C04 rs4282162 21426819 T 1567/183 0.503 0.525 1.09 0.42 C16 rs8050136 52373776 A 1567/183 0.411 0.402 0.96 0.72 C16 rs3751812 52375961 T 1567/184 0.410 0.402 0.97 0.78 C17 rs854793 17971249 A 1567/183 0.232 0.235 1.02 0.89 C10 rs4880711 5217871 C 1562/184 0.349 0.394 1.22 0.087 C12 rs12304836 124654446 C 1567/184 0.151 0.155 1.03 0.84 C05 rs38055 52596401 T 1567/184 0.340 0.315 0.89 0.34 C09 rs2297538 138684489 G 1555/180 0.791 0.789 0.99 0.91 C16 rs1870843 81316815 T 1567/184 0.603 0.587 0.94 0.55 C06 rs6905466 19958854 T 1567/183 0.338 0.342 1.02 0.89 C12 rs11045689 21092930 G 1557/182 0.346 0.288 0.76 0.025 C13 rs1887263 22381716 A 1567/184 0.174 0.193 1.13 0.38 C18 rs4271662 26051291 C 1567/183 0.595 0.617 1.10 0.41 C18 rs1365254 70238283 T 1567/184 0.187 0.168 0.88 0.39 C06 rs3016536 162157939 G 1567/183 0.596 0.579 0.93 0.54 C12 rs3742049 119438873 C 1565/183 0.885 0.888 1.03 0.86 C03 rs9874646 62437858 T 1567/183 0.669 0.699 1.15 0.24 C14 rs2281519 93846385 T 1564/183 0.267 0.235 0.84 0.18 C02 rs6747236 35901725 T 1566/184 0.755 0.726 0.86 0.21 C04 rs6534683 129601758 T 1567/183 0.652 0.628 0.90 0.37 C01 rs2991515 57656898 T 1565/184 0.458 0.438 0.92 0.44 C04 rs4697653 10337857 G 1553/182 0.567 0.569 1.01 0.95 C06 rs9380681 37638433 C 1567/183 0.315 0.328 1.06 0.62 C10 rs11199158 85297471 G 1566/183 0.645 0.623 0.91 0.41 C13 rs1375719 102208783 C 1566/183 0.492 0.516 1.10 0.37 C08 rs3931282 129179963 T 1567/184 0.517 0.514 0.99 0.9 C14 rs17776453 100774793 G 1567/183 0.956 0.967 1.37 0.28 C01 rs12724604 20948045 A 1566/184 0.044 0.019 0.42 0.011 C05 rs950195 97466690 G 1565/184 0.654 0.679 1.12 0.34 C05 rs728676 118087433 T 1567/183 0.462 0.429 0.87 0.22 C06 rs7739802 162154323 T 1567/183 0.549 0.530 0.92 0.48 C10 rs7086224 30857283 A 1567/184 0.418 0.459 1.18 0.13 C01 rs4845552 151746622 G 1567/183 0.125 0.107 0.83 0.3 C08 rs10504537 73402234 A 1567/184 0.866 0.851 0.88 0.43 C02 rs1395930 123468570 T 1567/183 0.539 0.481 0.79 0.035 C02 rs3943703 127613790 C 1558/181 0.228 0.240 1.07 0.61 C10 rs2279434 45275070 T 1567/184 0.075 0.065 0.86 0.48 C10 rs11198993 85244450 A 1566/183 0.786 0.790 1.02 0.86 C10 rs7921473 85156395 G 1567/183 0.844 0.863 1.17 0.33 C12 rs1465026 65789635 G 1564/184 0.836 0.832 0.97 0.81 C12 rs1568383 88017285 T 1567/183 0.117 0.134 1.17 0.36 C08 rs4732849 28249765 T 1566/184 0.310 0.318 1.04 0.76 C08 rs7006687 18277862 T 1567/183 0.558 0.557 1.00 0.99 C02 rs921083 176453128 G 1567/182 0.820 0.788 0.82 0.15 C02 rs6709904 43933828 A 1561/184 0.884 0.856 0.78 0.12 C14 rs1957860 53499105 T 1567/183 0.474 0.459 0.94 0.57 C14 rs4444235 53480669 T 1567/183 0.546 0.552 1.02 0.83 WTCCC (14246/1926) Replication (19396/5182) Chr nc/na Ctr. fr Aff. fr OR P OR (99% CI) P C06 14237/1924 0.173 0.197 1.17 0.00026 1.15 (1.08-1.22) 2.87E−05 C10 14223/1921 0.316 0.327 1.05 0.15 1.07 (1.00-1.14) 0.067 C10 1.09 (1.01-1.18) 0.026 C01 14220/1921 0.251 0.254 1.01 0.77 1.04 (0.99-1.10) 0.13 C11 13841/1882 0.482 0.488 1.02 0.53 1.03 (0.97-1.08) 0.34 C05 14239/1924 0.201 0.217 1.10 0.022 1.09 (1.01-1.18) 0.033 C17 14239/1924 0.350 0.347 0.99 0.7 1.03 (0.97-1.08) 0.34 C20 14220/1922 0.312 0.315 1.01 0.77 1.03 (0.98-1.09) 0.2 C05 14243/1925 0.182 0.196 1.09 0.046 1.06 (0.99-1.13) 0.11 C05 14239/1925 0.354 0.371 1.08 0.037 1.06 (1.01-1.12) 0.032 C19 1.01 (0.90-1.13) 0.86 C07 14243/1924 0.084 0.089 1.06 0.32 1.09 (1.00-1.19) 0.062 C17 14241/1925 0.375 0.370 0.98 0.53 1.02 (0.97-1.07) 0.41 C17 14215/1921 0.405 0.402 0.99 0.75 1.03 (0.98-1.08) 0.27 C14 1.04 (0.96-1.13) 0.31 C10 14219/1922 0.520 0.528 1.03 0.36 1.04 (0.98-1.11) 0.2 C17 14243/1925 0.350 0.346 0.99 0.69 1.02 (0.97-1.07) 0.46 C17 14242/1924 0.348 0.344 0.98 0.61 1.01 (0.96-1.07) 0.62 C17 14242/1925 0.394 0.395 1.00 0.9 1.02 (0.96-1.07) 0.57 C05 14242/1924 0.164 0.174 1.07 0.12 1.07 (0.98-1.16) 0.14 C07 14241/1925 0.096 0.099 1.03 0.62 1.06 (0.95-1.18) 0.31 C12 14243/1925 0.717 0.736 1.10 0.014 1.06 (1.00-1.12) 0.053 C20 14212/1921 0.397 0.407 1.04 0.21 1.04 (0.98-1.11) 0.21 C06 14241/1924 0.431 0.445 1.06 0.12 1.03 (0.98-1.09) 0.2 C07 14237/1924 0.252 0.263 1.06 0.14 1.04 (0.97-1.12) 0.29 C05 14228/1919 0.106 0.116 1.10 0.069 1.08 (0.98-1.20) 0.12 C15 14222/1922 0.074 0.076 1.04 0.54 1.05 (0.93-1.18) 0.46 C05 14228/1923 0.628 0.636 1.04 0.32 1.04 (0.98-1.12) 0.22 C05 14240/1924 0.290 0.301 1.06 0.13 1.06 (0.99-1.13) 0.12 C17 14240/1925 0.310 0.301 0.96 0.24 0.99 (0.94-1.05) 0.72 C11 14211/1921 0.510 0.520 1.04 0.28 1.04 (0.97-1.11) 0.26 C05 14240/1925 0.483 0.491 1.03 0.33 1.04 (0.98-1.10) 0.24 C17 14222/1922 0.333 0.330 0.98 0.63 1.00 (0.94-1.06) 0.96 C05 14233/1923 0.178 0.187 1.06 0.18 1.05 (0.96-1.14) 0.27 C05 14232/1924 0.301 0.314 1.07 0.084 1.03 (0.97-1.08) 0.32 C02 14218/1921 0.441 0.448 1.03 0.4 1.03 (0.98-1.09) 0.22 C01 14219/1922 0.560 0.560 1.00 0.97 1.00 (0.94-1.06) 0.99 C04 14242/1924 0.449 0.437 0.95 0.14 0.97 (0.92-1.03) 0.39 C05 14236/1924 0.607 0.628 1.09 0.013 1.03 (0.97-1.09) 0.29 C06 14241/1925 0.157 0.154 0.97 0.55 1.00 (0.92-1.08) 0.91 C05 14242/1925 0.945 0.946 1.03 0.68 1.04 (0.90-1.20) 0.59 C10 14240/1925 0.373 0.390 1.08 0.035 1.03 (0.97-1.08) 0.35 C15 14237/1925 0.058 0.059 1.02 0.78 1.00 (0.88-1.14) 0.98 C02 14239/1925 0.656 0.667 1.05 0.19 1.02 (0.97-1.08) 0.4 C14 14075/1906 0.153 0.162 1.07 0.18 1.04 (0.96-1.12) 0.34 C21 14236/1924 0.230 0.231 1.00 0.97 1.00 (0.93-1.08) 0.99 C05 14246/1925 0.193 0.212 1.13 0.0051 1.03 (0.96-1.10) 0.41 C08 14241/1924 0.928 0.920 0.89 0.084 0.94 (0.84-1.04) 0.23 C01 14238/1924 0.121 0.108 0.88 0.02 0.97 (0.89-1.05) 0.45 C13 14214/1921 0.474 0.471 0.99 0.72 1.00 (0.95-1.05) 1 C08 14242/1925 0.623 0.625 1.01 0.83 1.02 (0.96-1.09) 0.53 C08 14241/1925 0.623 0.625 1.01 0.83 1.02 (0.96-1.09) 0.53 C01 14236/1925 0.903 0.907 1.05 0.38 1.07 (0.95-1.19) 0.26 C04 14242/1924 0.506 0.505 0.99 0.84 1.00 (0.94-1.06) 0.97 C16 14192/1918 0.407 0.406 1.00 0.96 1.01 (0.95-1.07) 0.81 C16 14243/1925 0.406 0.406 1.00 0.99 1.01 (0.95-1.06) 0.82 C17 14222/1922 0.260 0.250 0.95 0.2 0.98 (0.92-1.04) 0.51 C10 14241/1925 0.377 0.380 1.01 0.73 1.03 (0.96-1.10) 0.4 C12 14234/1924 0.137 0.131 0.95 0.34 0.99 (0.92-1.07) 0.81 C05 14240/1924 0.317 0.319 1.01 0.82 1.02 (0.97-1.08) 0.35 C09 0.93 (0.84-1.04) 0.2 C16 14224/1922 0.637 0.638 1.00 0.91 1.00 (0.93-1.07) 0.94 C06 14224/1922 0.331 0.326 0.98 0.55 0.98 (0.92-1.05) 0.6 C12 14235/1924 0.356 0.358 1.01 0.84 1.01 (0.96-1.07) 0.75 C13 14241/1925 0.176 0.177 1.01 0.79 1.02 (0.94-1.11) 0.6 C18 14226/1922 0.597 0.599 1.01 0.81 1.01 (0.97-1.07) 0.56 C18 13709/1832 0.188 0.192 1.03 0.52 1.02 (0.93-1.10) 0.72 C06 14219/1921 0.628 0.628 1.00 0.99 0.99 (0.93-1.06) 0.87 C12 14239/1924 0.897 0.898 1.01 0.88 1.01 (0.92-1.11) 0.85 C03 14223/1921 0.670 0.669 0.99 0.84 1.01 (0.96-1.07) 0.63 C14 14234/1923 0.274 0.268 0.97 0.41 0.96 (0.89-1.03) 0.24 C02 14241/1924 0.762 0.754 0.96 0.29 0.97 (0.91-1.03) 0.35 C04 14230/1923 0.671 0.674 1.02 0.68 1.00 (0.94-1.08) 0.9 C01 14219/1921 0.399 0.392 0.97 0.38 0.97 (0.92-1.03) 0.37 C04 14229/1923 0.540 0.533 0.97 0.4 0.98 (0.93-1.03) 0.43 C06 14229/1923 0.365 0.362 0.99 0.73 0.99 (0.93-1.06) 0.85 C10 14246/1925 0.650 0.650 1.00 0.99 0.99 (0.94-1.05) 0.84 C13 14222/1922 0.510 0.510 1.00 0.95 0.99 (0.94-1.05) 0.84 C08 14236/1924 0.533 0.536 1.01 0.74 1.03 (0.98-1.09) 0.28 C14 14231/1923 0.923 0.923 1.00 0.97 1.01 (0.90-1.14) 0.85 C01 14244/1925 0.041 0.040 0.96 0.66 0.92 (0.78-1.08) 0.3 C05 14236/1924 0.649 0.647 0.99 0.82 0.97 (0.92-1.03) 0.34 C05 14223/1923 0.484 0.471 0.95 0.14 0.97 (0.92-1.02) 0.28 C06 14219/1922 0.624 0.620 0.98 0.64 0.98 (0.92-1.04) 0.51 C10 14217/1921 0.450 0.441 0.96 0.26 0.98 (0.92-1.04) 0.53 C01 14237/1924 0.139 0.135 0.97 0.51 0.95 (0.88-1.03) 0.23 C08 14233/1923 0.871 0.868 0.98 0.68 0.97 (0.88-1.07) 0.53 C02 14242/1925 0.498 0.495 0.99 0.71 0.98 (0.93-1.02) 0.32 C02 14171/1913 0.233 0.222 0.94 0.14 0.95 (0.88-1.03) 0.21 C10 14239/1924 0.085 0.081 0.95 0.42 0.92 (0.83-1.02) 0.11 C10 14241/1924 0.780 0.772 0.95 0.23 0.97 (0.91-1.03) 0.28 C10 14241/1923 0.857 0.845 0.91 0.05 0.93 (0.86-1.00) 0.054 C12 14240/1925 0.836 0.829 0.95 0.3 0.96 (0.89-1.03) 0.21 C12 14238/1924 0.111 0.104 0.92 0.14 0.93 (0.85-1.02) 0.12 C08 14240/1926 0.328 0.315 0.94 0.11 0.96 (0.91-1.02) 0.16 C08 14221/1922 0.556 0.550 0.97 0.44 0.94 (0.89-1.00) 0.034 C02 14215/1922 0.731 0.717 0.93 0.061 0.95 (0.90-1.01) 0.099 C02 14233/1924 0.900 0.896 0.96 0.47 0.94 (0.85-1.03) 0.19 C14 14238/1923 0.473 0.482 1.03 0.32 1.03 (0.98-1.08) 0.26 C14 14232/1923 0.537 0.536 0.99 0.86 0.98 (0.93-1.03) 0.36 Table 4F - CAD Pos in Build Hopkins (1567/389) Chr SNP 36 Allele nc/na Ctr. fr Aff. fr OR P C06 rs11751605 160883220 C 1565/389 0.155 0.180 1.20 0.093 C20 rs6076623 4084671 T 1567/388 0.296 0.331 1.18 0.059 C10 rs1412444 90992907 A 1565/388 0.321 0.345 1.11 0.2 C11 rs2163612 82856844 G 1566/387 0.497 0.506 1.04 0.63 C07 rs1029396 116812056 G 1566/388 0.080 0.110 1.42 0.0092 C10 rs2243547 91000459 G 1539/387 0.284 0.317 1.17 0.076 C07 rs12534186 117079572 T 1567/389 0.095 0.112 1.20 0.17 C01 rs12134779 63168930 T 1567/388 0.265 0.278 1.07 0.47 C14 rs7158073 99211442 T 1509/379 0.431 0.437 1.02 0.79 C05 rs254850 158599309 T 1567/389 0.195 0.190 0.97 0.76 C12 rs2417821 20081535 T 1566/389 0.728 0.729 1.00 0.98 C04 rs7661204 45728007 T 1567/388 0.410 0.374 0.86 0.064 C05 rs4921437 158623529 T 1566/388 0.184 0.182 0.98 0.87 C05 rs832540 56234959 C 1567/389 0.361 0.365 1.02 0.84 C07 rs324594 136305863 C 1567/387 0.269 0.267 0.99 0.92 C20 rs1741318 4105600 A 1566/388 0.377 0.374 0.99 0.88 C17 rs9902941 17674485 C 1567/387 0.367 0.368 1.00 0.96 C05 rs7709212 158696755 T 1567/388 0.674 0.700 1.13 0.17 C01 rs2946534 18647370 T 1564/388 0.548 0.581 1.15 0.092 C05 rs6556861 94554256 G 1567/388 0.623 0.610 0.94 0.48 C16 rs8050136 52373776 A 1567/388 0.411 0.418 1.03 0.75 C16 rs3751812 52375961 T 1567/389 0.410 0.418 1.03 0.68 C13 rs4769613 28036609 T 1567/388 0.469 0.514 1.20 0.024 C10 rs2243548 91000293 A 1566/388 0.504 0.522 1.07 0.38 C19 rs12459084 17031885 T 1512/381 0.415 0.423 1.03 0.69 C06 rs2074464 29516507 T 1562/388 0.447 0.452 1.02 0.77 C02 rs2244871 128115310 C 1556/385 0.426 0.425 0.99 0.94 C05 rs270654 158497687 G 1567/388 0.108 0.095 0.87 0.32 C17 rs854787 17975744 C 1552/385 0.428 0.429 1.00 0.96 C11 rs7944761 1361414 T 1567/389 0.563 0.539 0.90 0.21 C15 rs4779984 30302218 G 1562/388 0.125 0.121 0.96 0.76 C17 rs6502622 17775416 G 1563/388 0.401 0.397 0.99 0.85 C17 rs3183702 17688014 T 1561/388 0.365 0.365 1.00 0.99 C05 rs1433048 158688423 G 1565/388 0.184 0.178 0.96 0.67 C17 rs4925119 17683629 A 1542/383 0.361 0.362 1.00 0.97 C01 rs2476601 114179091 A 1566/388 0.091 0.097 1.07 0.63 C05 rs870347 6898035 T 1566/389 0.940 0.945 1.09 0.61 C08 rs334198 18933089 C 1566/389 0.922 0.914 0.89 0.43 C17 rs854813 17944570 C 1551/383 0.409 0.413 1.02 0.85 C06 rs7753765 71732495 A 1567/389 0.170 0.163 0.95 0.66 C17 rs4925114 17651995 A 1561/388 0.372 0.367 0.98 0.82 C05 rs270661 158492732 A 1567/389 0.194 0.179 0.91 0.34 C05 rs953861 158705160 G 1565/389 0.168 0.162 0.95 0.67 C05 rs10045431 158747111 A 1567/389 0.289 0.298 1.04 0.62 C14 rs8003722 68388015 A 1566/388 0.138 0.146 1.07 0.57 C09 rs2297538 138684489 G 1555/381 0.791 0.797 1.03 0.75 C02 rs12329252 212093968 T 1567/388 0.657 0.680 1.11 0.22 C01 rs3748744 19828833 G 1561/387 0.896 0.898 1.03 0.85 C05 rs4704400 76586766 T 1563/388 0.485 0.476 0.96 0.64 C08 rs3102526 96858538 G 1565/388 0.620 0.628 1.03 0.69 C15 rs2110209 24946433 A 1567/389 0.031 0.030 0.94 0.8 C16 rs1870843 81316815 T 1567/389 0.603 0.603 1.00 0.99 C08 rs3134517 96859237 G 1567/389 0.620 0.627 1.03 0.7 C21 rs2828495 24038081 A 1566/388 0.233 0.201 0.83 0.056 C04 rs4282162 21426819 T 1567/388 0.503 0.503 1.00 1 C17 rs2955355 17889200 C 1565/388 0.318 0.326 1.04 0.65 C12 rs11045689 21092930 G 1557/386 0.346 0.325 0.91 0.26 C05 rs7447732 158461713 C 1566/389 0.321 0.319 0.99 0.91 C18 rs1365254 70238283 T 1567/389 0.187 0.180 0.96 0.67 C13 rs1887263 22381716 A 1567/389 0.174 0.180 1.04 0.71 C12 rs12304836 124654446 C 1567/389 0.151 0.138 0.90 0.34 C05 rs38055 52596401 T 1567/389 0.340 0.324 0.93 0.39 C04 rs4697653 10337857 G 1553/386 0.567 0.580 1.06 0.5 C05 rs728676 118087433 T 1567/388 0.462 0.461 1.00 0.96 C06 rs6905466 19958854 T 1567/388 0.338 0.335 0.99 0.88 C10 rs11199158 85297471 G 1566/388 0.645 0.621 0.90 0.22 C01 rs4845552 151746622 G 1567/388 0.125 0.117 0.93 0.55 C02 rs1395930 123468570 T 1567/388 0.539 0.514 0.91 0.22 C04 rs6534683 129601758 T 1567/388 0.652 0.635 0.93 0.38 C02 rs6747236 35901725 T 1566/389 0.755 0.754 0.99 0.96 C06 rs3016536 162157939 G 1567/388 0.596 0.573 0.91 0.26 C10 rs12269612 15475877 T 1567/389 0.376 0.362 0.94 0.49 C17 rs854793 17971249 A 1567/388 0.232 0.237 1.03 0.75 C12 rs3742049 119438873 C 1565/388 0.885 0.879 0.94 0.64 C01 rs2991515 57656898 T 1565/389 0.458 0.428 0.88 0.13 C18 rs4271662 26051291 C 1567/388 0.595 0.601 1.02 0.78 C06 rs7739802 162154323 T 1567/388 0.549 0.531 0.93 0.35 C08 rs10504537 73402234 A 1567/388 0.866 0.865 0.99 0.94 C14 rs17776453 100774793 G 1567/388 0.956 0.954 0.95 0.81 C10 rs7086224 30857283 A 1567/389 0.418 0.450 1.14 0.11 C01 rs12724604 20948045 A 1566/389 0.044 0.037 0.83 0.37 C03 rs9874646 62437858 T 1567/388 0.669 0.673 1.01 0.86 C05 rs950195 97466690 G 1565/389 0.654 0.657 1.01 0.9 C14 rs2281519 93846385 T 1564/388 0.267 0.254 0.93 0.45 C10 rs4880711 5217871 C 1562/388 0.349 0.343 0.97 0.76 C08 rs3931282 129179963 T 1567/389 0.517 0.528 1.05 0.57 C10 rs11198993 85244450 A 1566/388 0.786 0.764 0.88 0.2 C12 rs1568383 88017285 T 1567/388 0.117 0.125 1.08 0.54 C06 rs9380681 37638433 C 1567/388 0.315 0.325 1.04 0.61 C02 rs6709904 43933828 A 1561/388 0.884 0.871 0.88 0.31 C10 rs2279434 45275070 T 1567/389 0.075 0.077 1.03 0.86 C13 rs1375719 102208783 C 1566/388 0.492 0.492 1.00 0.98 C10 rs7921473 85156395 G 1567/387 0.844 0.840 0.97 0.76 C14 rs1957860 53499105 T 1567/388 0.474 0.481 1.03 0.76 C02 rs3943703 127613790 C 1558/385 0.228 0.232 1.02 0.81 C08 rs7006687 18277862 T 1567/388 0.558 0.550 0.97 0.71 C12 rs1465026 65789635 G 1564/389 0.836 0.832 0.97 0.75 C14 rs4444235 53480669 T 1567/388 0.546 0.523 0.91 0.26 C02 rs921083 176453128 G 1567/387 0.820 0.796 0.86 0.12 C08 rs4732849 28249765 T 1566/389 0.310 0.320 1.05 0.59 WTCCC (14246/1926) Replication (19396/6108) Chr nc/na Ctr. fr Aff. fr OR P OR (95% CI) P C06 14237/1924 0.173 0.197 1.17 0.00026 1.15 (1.08-1.22) 7.33E−06 C20 14220/1922 0.312 0.315 1.01 0.77 1.04 (0.99-1.09) 0.12 C10 1.09 (1.02-1.17) 0.013 C11 13841/1882 0.482 0.488 1.02 0.53 1.03 (0.98-1.09) 0.2 C07 14243/1924 0.084 0.089 1.06 0.32 1.08 (0.99-1.18) 0.066 C10 14223/1921 0.316 0.327 1.05 0.15 1.07 (1.00-1.14) 0.045 C07 14241/1925 0.096 0.099 1.03 0.62 1.05 (0.95-1.17) 0.31 C01 14220/1921 0.251 0.254 1.01 0.77 1.04 (0.99-1.10) 0.1 C14 1.05 (0.98-1.13) 0.15 C05 14239/1924 0.201 0.217 1.10 0.022 1.08 (1.00-1.17) 0.045 C12 14243/1925 0.717 0.736 1.10 0.014 1.06 (1.00-1.12) 0.057 C04 14242/1924 0.449 0.437 0.95 0.14 0.96 (0.91-1.02) 0.21 C05 14243/1925 0.182 0.196 1.09 0.046 1.05 (0.99-1.13) 0.11 C05 14239/1925 0.354 0.371 1.08 0.037 1.05 (1.00-1.11) 0.074 C07 14237/1924 0.252 0.263 1.06 0.14 1.05 (0.98-1.12) 0.19 C20 14212/1921 0.397 0.407 1.04 0.21 1.04 (0.97-1.10) 0.28 C17 14239/1924 0.350 0.347 0.99 0.7 1.03 (0.98-1.08) 0.27 C05 14228/1923 0.628 0.636 1.04 0.32 1.05 (0.98-1.12) 0.15 C01 14219/1922 0.560 0.560 1.00 0.97 1.02 (0.96-1.08) 0.54 C05 14236/1924 0.607 0.628 1.09 0.013 1.04 (0.99-1.10) 0.14 C16 14192/1918 0.407 0.406 1.00 0.96 1.02 (0.96-1.07) 0.56 C16 14243/1925 0.406 0.406 1.00 0.99 1.02 (0.96-1.07) 0.58 C13 14214/1921 0.474 0.471 0.99 0.72 1.01 (0.96-1.06) 0.77 C10 14219/1922 0.520 0.528 1.03 0.36 1.04 (0.98-1.10) 0.24 C19 1.00 (0.91-1.11) 0.94 C06 14241/1924 0.431 0.445 1.06 0.12 1.03 (0.98-1.08) 0.23 C02 14218/1921 0.441 0.448 1.03 0.4 1.04 (0.98-1.09) 0.17 C05 14228/1919 0.106 0.116 1.10 0.069 1.07 (0.97-1.18) 0.19 C17 14215/1921 0.405 0.402 0.99 0.75 1.03 (0.98-1.08) 0.3 C11 14211/1921 0.510 0.520 1.04 0.28 1.02 (0.96-1.08) 0.61 C15 14222/1922 0.074 0.076 1.04 0.54 1.02 (0.91-1.14) 0.69 C17 14241/1925 0.375 0.370 0.98 0.53 1.02 (0.97-1.07) 0.47 C17 14242/1924 0.348 0.344 0.98 0.61 1.01 (0.96-1.06) 0.6 C05 14233/1923 0.178 0.187 1.06 0.18 1.04 (0.96-1.13) 0.29 C17 14243/1925 0.350 0.346 0.99 0.69 1.02 (0.97-1.07) 0.5 C01 14238/1924 0.121 0.108 0.88 0.02 0.98 (0.91-1.06) 0.68 C05 14242/1925 0.945 0.946 1.03 0.68 1.04 (0.91-1.19) 0.56 C08 14241/1924 0.928 0.920 0.89 0.084 0.92 (0.83-1.02) 0.11 C17 14242/1925 0.394 0.395 1.00 0.9 1.02 (0.97-1.07) 0.54 C06 14241/1925 0.157 0.154 0.97 0.55 0.97 (0.90-1.05) 0.5 C17 14222/1922 0.333 0.330 0.98 0.63 1.01 (0.95-1.07) 0.82 C05 14246/1925 0.193 0.212 1.13 0.0051 1.03 (0.97-1.10) 0.29 C05 14242/1924 0.164 0.174 1.07 0.12 1.05 (0.97-1.15) 0.21 C05 14240/1924 0.290 0.301 1.06 0.13 1.06 (0.99-1.13) 0.11 C14 14075/1906 0.153 0.162 1.07 0.18 1.04 (0.97-1.12) 0.28 C09 0.96 (0.87-1.05) 0.34 C02 14239/1925 0.656 0.667 1.05 0.19 1.02 (0.97-1.07) 0.53 C01 14236/1925 0.903 0.907 1.05 0.38 1.05 (0.94-1.16) 0.38 C05 14240/1925 0.483 0.491 1.03 0.33 1.02 (0.96-1.08) 0.49 C08 14242/1925 0.623 0.625 1.01 0.83 1.01 (0.95-1.08) 0.72 C15 14237/1925 0.058 0.059 1.02 0.78 1.00 (0.88-1.14) 0.96 C16 14224/1922 0.637 0.638 1.00 0.91 1.00 (0.94-1.07) 0.92 C08 14241/1925 0.623 0.625 1.01 0.83 1.01 (0.95-1.08) 0.72 C21 14236/1924 0.230 0.231 1.00 0.97 0.97 (0.90-1.05) 0.48 C04 14242/1924 0.506 0.505 0.99 0.84 1.00 (0.94-1.05) 0.87 C17 14240/1925 0.310 0.301 0.96 0.24 0.99 (0.94-1.04) 0.64 C12 14235/1924 0.356 0.358 1.01 0.84 1.01 (0.96-1.07) 0.63 C05 14232/1924 0.301 0.314 1.07 0.084 1.01 (0.96-1.06) 0.68 C18 13709/1832 0.188 0.192 1.03 0.52 1.02 (0.94-1.10) 0.68 C13 14241/1925 0.176 0.177 1.01 0.79 1.02 (0.94-1.10) 0.69 C12 14234/1924 0.137 0.131 0.95 0.34 0.98 (0.91-1.05) 0.53 C05 14240/1924 0.317 0.319 1.01 0.82 1.02 (0.97-1.07) 0.42 C04 14229/1923 0.540 0.533 0.97 0.4 1.00 (0.95-1.05) 0.91 C05 14223/1923 0.484 0.471 0.95 0.14 0.98 (0.93-1.03) 0.45 C06 14224/1922 0.331 0.326 0.98 0.55 0.98 (0.92-1.05) 0.55 C10 14246/1925 0.650 0.650 1.00 0.99 0.99 (0.94-1.05) 0.78 C01 14237/1924 0.139 0.135 0.97 0.51 0.96 (0.90-1.04) 0.33 C02 14242/1925 0.498 0.495 0.99 0.71 0.98 (0.93-1.02) 0.29 C04 14230/1923 0.671 0.674 1.02 0.68 1.00 (0.94-1.07) 0.98 C02 14241/1924 0.762 0.754 0.96 0.29 0.99 (0.93-1.05) 0.71 C06 14219/1921 0.628 0.628 1.00 0.99 0.99 (0.93-1.05) 0.67 C10 14240/1925 0.373 0.390 1.08 0.035 1.00 (0.95-1.05) 0.98 C17 14222/1922 0.260 0.250 0.95 0.2 0.98 (0.93-1.04) 0.53 C12 14239/1924 0.897 0.898 1.01 0.88 1.00 (0.91-1.09) 0.96 C01 14219/1921 0.399 0.392 0.97 0.38 0.96 (0.91-1.02) 0.2 C18 14226/1922 0.597 0.599 1.01 0.81 1.01 (0.96-1.06) 0.65 C06 14219/1922 0.624 0.620 0.98 0.64 0.97 (0.91-1.04) 0.42 C08 14233/1923 0.871 0.868 0.98 0.68 0.98 (0.90-1.08) 0.69 C14 14231/1923 0.923 0.923 1.00 0.97 0.99 (0.88-1.12) 0.91 C10 14217/1921 0.450 0.441 0.96 0.26 0.99 (0.93-1.05) 0.68 C01 14244/1925 0.041 0.040 0.96 0.66 0.94 (0.80-1.10) 0.45 C03 14223/1921 0.670 0.669 0.99 0.84 1.01 (0.96-1.07) 0.72 C05 14236/1924 0.649 0.647 0.99 0.82 0.97 (0.92-1.02) 0.24 C14 14234/1923 0.274 0.268 0.97 0.41 0.96 (0.90-1.03) 0.29 C10 14241/1925 0.377 0.380 1.01 0.73 1.01 (0.94-1.07) 0.84 C08 14236/1924 0.533 0.536 1.01 0.74 1.04 (0.98-1.09) 0.19 C10 14241/1924 0.780 0.772 0.95 0.23 0.95 (0.89-1.01) 0.095 C12 14238/1924 0.111 0.104 0.92 0.14 0.93 (0.85-1.02) 0.11 C06 14229/1923 0.365 0.362 0.99 0.73 1.00 (0.93-1.06) 0.91 C02 14233/1924 0.900 0.896 0.96 0.47 0.95 (0.87-1.04) 0.24 C10 14239/1924 0.085 0.081 0.95 0.42 0.93 (0.85-1.03) 0.19 C13 14222/1922 0.510 0.510 1.00 0.95 0.98 (0.93-1.04) 0.49 C10 14241/1923 0.857 0.845 0.91 0.05 0.93 (0.87-1.00) 0.036 C14 14238/1923 0.473 0.482 1.03 0.32 1.03 (0.98-1.09) 0.19 C02 14171/1913 0.233 0.222 0.94 0.14 0.95 (0.89-1.03) 0.21 C08 14221/1922 0.556 0.550 0.97 0.44 0.94 (0.90-0.99) 0.024 C12 14240/1925 0.836 0.829 0.95 0.3 0.95 (0.89-1.02) 0.17 C14 14232/1923 0.537 0.536 0.99 0.86 0.97 (0.92-1.02) 0.18 C02 14215/1922 0.731 0.717 0.93 0.061 0.95 (0.90-1.01) 0.089 C08 14240/1926 0.328 0.315 0.94 0.11 0.97 (0.92-1.02) 0.21 Table 4G - MI Iceland (28321/2395) Combined (47717/7577) Chr SNP Pos_B36 Allele nc/na Ctr. fr Aff. fr OR P OR (95% CI) P C06 rs11751605 160883220 C 28085/2387 0.111 0.128 1.18 0.00098 1.16 (1.10-1.22) 1.11E−07 C10 rs2243547 91000459 G 28033/2386 0.331 0.363 1.15 2.71E−05 1.11 (1.06-1.16) 1.81E−05 C10 rs1412444 90992907 A 28293/2394 0.361 0.389 1.13 0.00037 1.11 (1.06-1.17) 3.30E−05 C01 rs12134779 63168930 T 28320/2394 0.292 0.325 1.17 9.41E−06 1.09 (1.04-1.14) 8.32E−05 C11 rs2163612 82856844 G 28294/2393 0.479 0.519 1.17 1.01E−06 1.08 (1.04-1.13) 0.00011 C05 rs254850 158599309 T 28316/2395 0.220 0.242 1.13 0.0011 1.11 (1.05-1.18) 0.00013 C17 rs9902941 17674485 C 28319/2395 0.347 0.384 1.17 2.90E−06 1.08 (1.04-1.13) 0.00023 C20 rs6076623 4084671 T 28302/2395 0.367 0.399 1.15 4.51E−05 1.08 (1.03-1.12) 0.0004 C05 rs4921437 158623529 T 28259/2386 0.216 0.240 1.14 0.00049 1.10 (1.04-1.15) 0.00041 C05 rs832540 56234959 C 28307/2395 0.422 0.444 1.09 0.0061 1.08 (1.03-1.12) 0.00063 C19 rs12459084 17031885 T 27962/2387 0.350 0.380 1.14 0.00013 1.10 (1.04-1.17) 0.00071 C07 rs1029396 116812056 G 28315/2395 0.071 0.084 1.21 0.0018 1.13 (1.05-1.21) 0.00076 C17 rs6502622 17775416 G 28303/2395 0.358 0.393 1.16 6.50E−06 1.07 (1.03-1.11) 0.00078 C17 rs854787 17975744 C 28104/2381 0.400 0.432 1.14 4.64E−05 1.07 (1.03-1.11) 0.0008 C14 rs7158073 99211442 T 28102/2379 0.430 0.458 1.12 0.0005 1.09 (1.04-1.14) 0.00083 C10 rs2243548 91000293 A 28294/2392 0.512 0.540 1.12 0.0007 1.08 (1.03-1.13) 0.0009 C17 rs4925119 17683629 A 28218/2387 0.345 0.380 1.16 7.74E−06 1.07 (1.03-1.11) 0.0011 C17 rs3183702 17688014 T 28108/2388 0.348 0.384 1.17 4.13E−06 1.07 (1.03-1.11) 0.0012 C17 rs854813 17944570 C 28182/2393 0.385 0.420 1.16 1.06E−05 1.07 (1.03-1.11) 0.0013 C05 rs953861 158705160 G 28318/2395 0.161 0.180 1.14 0.0027 1.10 (1.04-1.17) 0.0014 C07 rs12534186 117079572 T 28310/2394 0.081 0.096 1.22 0.00056 1.13 (1.05-1.22) 0.0017 C12 rs2417821 20081535 T 28317/2395 0.754 0.771 1.10 0.014 1.07 (1.03-1.13) 0.0023 C20 rs1741318 4105600 A 28315/2394 0.450 0.474 1.10 0.0025 1.07 (1.03-1.12) 0.0024 C06 rs2074464 29516507 T 28296/2392 0.446 0.471 1.11 0.0015 1.06 (1.02-1.10) 0.0031 C07 rs324594 136305863 C 28310/2395 0.266 0.289 1.12 0.0023 1.08 (1.03-1.14) 0.0033 C05 rs270654 158497687 G 28318/2395 0.137 0.151 1.12 0.012 1.11 (1.03-1.18) 0.0036 C15 rs4779984 30302218 G 28236/2392 0.100 0.116 1.18 0.0015 1.12 (1.04-1.21) 0.0038 C05 rs7709212 158696755 T 28305/2394 0.680 0.702 1.11 0.004 1.07 (1.02-1.13) 0.0039 C05 rs10045431 158747111 A 28238/2364 0.266 0.285 1.10 0.011 1.08 (1.02-1.13) 0.0039 C17 rs2955355 17889200 C 28312/2395 0.285 0.321 1.19 8.68E−07 1.06 (1.02-1.11) 0.005 C11 rs7944761 1361414 T 28309/2395 0.532 0.555 1.09 0.0053 1.07 (1.02-1.12) 0.0057 C05 rs4704400 76586766 T 28306/2394 0.498 0.520 1.09 0.0057 1.06 (1.02-1.11) 0.006 C17 rs4925114 17651995 A 28266/2391 0.357 0.389 1.15 4.55E−05 1.06 (1.02-1.11) 0.006 C05 rs1433048 158688423 G 27899/2344 0.193 0.211 1.11 0.0074 1.08 (1.02-1.15) 0.0069 C05 rs7447732 158461713 C 28280/2393 0.320 0.343 1.11 0.0033 1.06 (1.01-1.10) 0.0098 C02 rs2244871 128115310 C 28251/2394 0.413 0.433 1.08 0.013 1.06 (1.01-1.10) 0.011 C01 rs2946534 18647370 T 28302/2394 0.571 0.599 1.12 0.00034 1.06 (1.01-1.11) 0.012 C04 rs7661204 45728007 T 28320/2395 0.449 0.427 0.91 0.0055 0.95 (0.91-0.99) 0.012 C05 rs6556861 94554256 G 28317/2395 0.570 0.591 1.09 0.0082 1.06 (1.01-1.10) 0.012 C06 rs7753765 71732495 A 28312/2395 0.144 0.166 1.18 0.00014 1.08 (1.01-1.14) 0.014 C05 rs870347 6898035 T 28313/2395 0.926 0.937 1.20 0.0052 1.12 (1.02-1.24) 0.015 C10 rs12269612 15475877 T 28314/2395 0.401 0.423 1.09 0.0078 1.05 (1.01-1.10) 0.015 C15 rs2110209 24946433 A 28318/2395 0.048 0.061 1.28 0.00051 1.12 (1.02-1.23) 0.018 C02 rs12329252 212093968 T 28321/2395 0.681 0.703 1.10 0.0047 1.05 (1.01-1.09) 0.019 C14 rs8003722 68388015 A 28317/2394 0.106 0.119 1.14 0.0085 1.07 (1.01-1.14) 0.019 C21 rs2828495 24038081 A 28316/2395 0.212 0.234 1.14 0.001 1.07 (1.01-1.12) 0.021 C05 rs270661 158492732 A 28319/2394 0.210 0.227 1.10 0.011 1.06 (1.01-1.12) 0.022 C08 rs334198 18933089 C 28309/2393 0.922 0.913 0.89 0.037 0.91 (0.84-0.99) 0.022 C01 rs2476601 114179091 A 28313/2395 0.129 0.152 1.21 3.14E−05 1.07 (1.01-1.14) 0.024 C13 rs4769613 28036609 T 28313/2394 0.465 0.494 1.12 0.00041 1.05 (1.01-1.09) 0.024 C08 rs3102526 96858538 G 27995/2382 0.647 0.666 1.09 0.013 1.05 (1.01-1.10) 0.029 C08 rs3134517 96859237 G 28308/2395 0.647 0.666 1.09 0.016 1.05 (1.00-1.10) 0.032 C01 rs3748744 19828833 G 28280/2394 0.898 0.907 1.11 0.063 1.09 (1.01-1.17) 0.034 C04 rs4282162 21426819 T 28305/2395 0.530 0.555 1.11 0.002 1.05 (1.00-1.09) 0.036 C16 rs8050136 52373776 A 28316/2394 0.404 0.426 1.10 0.0046 1.05 (1.00-1.09) 0.039 C16 rs3751812 52375961 T 28246/2392 0.403 0.426 1.10 0.0041 1.05 (1.00-1.09) 0.039 C17 rs854793 17971249 A 28313/2395 0.202 0.229 1.18 3.33E−05 1.05 (1.00-1.10) 0.041 C10 rs4880711 5217871 C 27953/2379 0.351 0.367 1.07 0.042 1.05 (1.00-1.10) 0.043 C12 rs12304836 124654446 C 28205/2385 0.143 0.163 1.17 0.00054 1.06 (1.00-1.12) 0.043 C05 rs38055 52596401 T 28311/2395 0.387 0.403 1.07 0.052 1.04 (1.00-1.08) 0.053 C09 rs2297538 138684489 G 28226/2395 0.730 0.753 1.13 0.0012 1.06 (1.00-1.13) 0.053 C16 rs1870843 81316815 T 28313/2395 0.602 0.623 1.09 0.0081 1.05 (1.00-1.10) 0.064 C06 rs6905466 19958854 T 28315/2395 0.332 0.355 1.11 0.0027 1.04 (1.00-1.10) 0.074 C12 rs11045689 21092930 G 28210/2386 0.301 0.319 1.09 0.017 1.04 (1.00-1.08) 0.083 C13 rs1887263 22381716 A 28175/2393 0.204 0.216 1.08 0.067 1.05 (0.99-1.11) 0.089 C18 rs4271662 26051291 C 28256/2390 0.587 0.602 1.06 0.061 1.03 (0.99-1.07) 0.11 C18 rs1365254 70238283 T 28319/2395 0.196 0.208 1.08 0.066 1.05 (0.99-1.11) 0.11 C06 rs3016536 162157939 G 28320/2395 0.519 0.538 1.08 0.02 1.04 (0.99-1.08) 0.12 C12 rs3742049 119438873 C 28300/2394 0.919 0.928 1.14 0.029 1.06 (0.98-1.14) 0.13 C03 rs9874646 62437858 T 28314/2394 0.717 0.729 1.06 0.11 1.03 (0.99-1.08) 0.17 C14 rs2281519 93846385 T 28281/2395 0.260 0.282 1.12 0.0023 1.04 (0.98-1.09) 0.17 C02 rs6747236 35901725 T 28311/2395 0.717 0.739 1.12 0.0021 1.03 (0.98-1.08) 0.18 C04 rs6534683 129601758 T 28310/2395 0.656 0.670 1.06 0.076 1.03 (0.99-1.08) 0.18 C01 rs2991515 57656898 T 28319/2395 0.483 0.507 1.10 0.0033 1.03 (0.99-1.07) 0.19 C04 rs4697653 10337857 G 28161/2392 0.524 0.549 1.11 0.0021 1.03 (0.99-1.07) 0.19 C06 rs9380681 37638433 C 28318/2395 0.311 0.327 1.08 0.038 1.03 (0.98-1.08) 0.19 C10 rs11199158 85297471 G 28319/2395 0.618 0.635 1.08 0.024 1.03 (0.99-1.08) 0.19 C13 rs1375719 102208783 C 28316/2394 0.499 0.517 1.07 0.032 1.03 (0.99-1.08) 0.19 C08 rs3931282 129179963 T 28319/2395 0.568 0.543 0.90 0.0016 0.97 (0.93-1.02) 0.21 C14 rs17776453 100774793 G 28313/2394 0.955 0.961 1.15 0.095 1.06 (0.96-1.17) 0.24 C01 rs12724604 20948045 A 28248/2386 0.037 0.045 1.23 0.0098 1.07 (0.95-1.20) 0.25 C05 rs950195 97466690 G 28228/2395 0.633 0.656 1.10 0.0033 1.03 (0.98-1.07) 0.25 C05 rs728676 118087433 T 28310/2394 0.444 0.468 1.10 0.0023 1.02 (0.98-1.07) 0.25 C06 rs7739802 162154323 T 28266/2393 0.493 0.511 1.07 0.027 1.03 (0.98-1.08) 0.26 C10 rs7086224 30857283 A 28287/2393 0.419 0.437 1.08 0.028 1.03 (0.98-1.07) 0.27 C01 rs4845552 151746622 G 28269/2393 0.128 0.145 1.15 0.0025 1.03 (0.97-1.09) 0.3 C08 rs10504537 73402234 A 28213/2387 0.881 0.891 1.11 0.035 1.04 (0.97-1.11) 0.32 C02 rs1395930 123468570 T 28303/2393 0.499 0.523 1.10 0.0032 1.02 (0.98-1.06) 0.33 C02 rs3943703 127613790 C 28280/2395 0.214 0.229 1.09 0.02 1.02 (0.97-1.08) 0.44 C10 rs2279434 45275070 T 28318/2395 0.067 0.080 1.20 0.0029 1.03 (0.95-1.12) 0.46 C10 rs11198993 85244450 A 28239/2387 0.697 0.714 1.08 0.022 1.02 (0.97-1.07) 0.46 C10 rs7921473 85156395 G 28314/2395 0.820 0.840 1.15 0.0011 1.02 (0.96-1.08) 0.51 C12 rs1465026 65789635 G 28309/2395 0.837 0.852 1.12 0.011 1.02 (0.96-1.08) 0.52 C12 rs1568383 88017285 T 28316/2395 0.098 0.111 1.15 0.008 1.02 (0.95-1.09) 0.55 C08 rs4732849 28249765 T 28321/2395 0.275 0.295 1.10 0.0069 1.01 (0.97-1.06) 0.56 C08 rs7006687 18277862 T 28306/2392 0.579 0.604 1.11 0.0018 1.01 (0.97-1.05) 0.73 C02 rs921083 176453128 G 28310/2394 0.781 0.798 1.11 0.0092 1.01 (0.96-1.06) 0.78 C02 rs6709904 43933828 A 28315/2395 0.909 0.918 1.12 0.058 1.01 (0.94-1.08) 0.84 C14 rs1957860 53499105 T 28313/2395 0.448 0.439 0.96 0.27 1.00 (0.96-1.04) 0.86 C14 rs4444235 53480669 T 28305/2394 0.536 0.543 1.03 0.37 1.00 (0.96-1.04) 0.88 Table 4H - CAD Pos in Iceland (28321/3047) Combined (47717/9155) Chr SNP Build 36 Allele nc/na Ctr. fr Aff. fr OR P OR (95% CI) P C06 rs11751605 160883220 C 28085/3033 0.111 0.128 1.17 0.00039 1.16 (1.10-1.22) 1.16E−08 C20 rs6076623 4084671 T 28302/3047 0.367 0.400 1.15 3.56E−06 1.08 (1.04-1.13) 0.0000292 C10 rs1412444 90992907 A 28293/3045 0.361 0.383 1.10 0.0014 1.10 (1.05-1.15) 5.21E−05 C11 rs2163612 82856844 G 28294/3045 0.479 0.513 1.15 3.61E−06 1.08 (1.04-1.12) 0.0000533 C07 rs1029396 116812056 G 28315/3047 0.071 0.086 1.24 0.0000612 1.14 (1.07-1.22) 0.0000824 C10 rs2243547 91000459 G 28033/3033 0.331 0.355 1.11 6.60E−04 1.09 (1.04-1.14) 1.10E−04 C07 rs12534186 117079572 T 28310/3046 0.081 0.098 1.24 0.0000302 1.15 (1.07-1.23) 0.00021 C01 rs12134779 63168930 T 28320/3046 0.292 0.316 1.12 2.80E−04 1.07 (1.03-1.12) 3.70E−04 C14 rs7158073 99211442 T 28102/3027 0.430 0.453 1.10 0.0016 1.08 (1.03-1.13) 0.00076 C05 rs254850 158599309 T 28316/3047 0.220 0.236 1.10 0.0082 1.09 (1.04-1.15) 0.00095 C12 rs2417821 20081535 T 28317/3047 0.754 0.772 1.10 0.0042 1.08 (1.03-1.12) 0.001 C04 rs7661204 45728007 T 28320/3047 0.449 0.425 0.91 0.00074 0.94 (0.90-0.97) 0.0011 C05 rs4921437 158623529 T 28259/3037 0.216 0.235 1.11 0.0022 1.08 (1.03-1.13) 0.0011 C05 rs832540 56234959 C 28307/3047 0.422 0.443 1.09 0.0043 1.07 (1.03-1.11) 0.0012 C07 rs324594 136305863 C 28310/3047 0.266 0.287 1.11 0.0018 1.08 (1.03-1.13) 0.0014 C20 rs1741318 4105600 A 28315/3046 0.450 0.473 1.10 0.0013 1.07 (1.03-1.12) 0.0019 C17 rs9902941 17674485 C 28319/3047 0.347 0.371 1.11 9.50E−04 1.06 (1.02-1.10) 0.0028 C05 rs7709212 158696755 T 28305/3046 0.680 0.699 1.09 0.0061 1.07 (1.02-1.12) 0.0029 C01 rs2946534 18647370 T 28302/3046 0.571 0.596 1.11 0.00045 1.07 (1.02-1.11) 0.0032 C05 rs6556861 94554256 G 28317/3047 0.570 0.590 1.08 0.006 1.06 (1.02-1.10) 0.0034 C16 rs8050136 52373776 A 28316/3046 0.404 0.430 1.11 0.00029 1.06 (1.02-1.10) 0.0038 C16 rs3751812 52375961 T 28246/3044 0.403 0.430 1.12 0.00024 1.06 (1.02-1.10) 0.004 C13 rs4769613 28036609 T 28313/3046 0.465 0.493 1.12 0.00013 1.05 (1.02-1.10) 0.0059 C10 rs2243548 91000293 A 28294/3043 0.512 0.532 1.08 0.0087 1.06 (1.02-1.11) 0.0064 C19 rs12459084 17031885 T 27962/3037 0.350 0.372 1.10 0.002 1.07 (1.02-1.13) 0.0067 C06 rs2074464 29516507 T 28296/3044 0.446 0.466 1.08 0.006 1.05 (1.01-1.09) 0.0076 C02 rs2244871 128115310 C 28251/3046 0.413 0.430 1.08 0.015 1.05 (1.01-1.10) 0.0079 C05 rs270654 158497687 G 28318/3047 0.137 0.149 1.10 0.021 1.09 (1.02-1.16) 0.0092 C17 rs854787 17975744 C 28104/3028 0.400 0.420 1.09 4.60E−03 1.05 (1.01-1.09) 0.0097 C11 rs7944761 1361414 T 28309/3047 0.532 0.554 1.09 0.0027 1.06 (1.01-1.10) 0.011 C15 rs4779984 30302218 G 28236/3043 0.100 0.114 1.15 0.003 1.10 (1.02-1.18) 0.011 C17 rs6502622 17775416 G 28303/3047 0.358 0.380 1.10 1.90E−03 1.05 (1.01-1.09) 0.013 C17 rs3183702 17688014 T 28108/3038 0.348 0.371 1.10 1.30E−03 1.05 (1.01-1.09) 0.014 C05 rs1433048 158688423 G 27899/2989 0.193 0.207 1.09 0.021 1.07 (1.01-1.13) 0.015 C17 rs4925119 17683629 A 28218/3036 0.345 0.367 1.10 2.10E−03 1.05 (1.01-1.09) 0.015 C01 rs2476601 114179091 A 28313/3047 0.129 0.148 1.18 9.72E−05 1.07 (1.01-1.14) 0.016 C05 rs870347 6898035 T 28313/3047 0.926 0.936 1.17 0.0088 1.11 (1.02-1.21) 0.017 C08 rs334198 18933089 C 28309/3045 0.922 0.915 0.91 0.082 0.92 (0.85-0.98) 0.018 C17 rs854813 17944570 C 28182/3042 0.385 0.406 1.09 3.10E−03 1.05 (1.01-1.09) 0.018 C06 rs7753765 71732495 A 28312/3047 0.144 0.165 1.18 0.0000474 1.07 (1.01-1.13) 0.02 C17 rs4925114 17651995 A 28266/3042 0.357 0.379 1.10 1.70E−03 1.05 (1.01-1.09) 0.02 C05 rs270661 158492732 A 28319/3046 0.210 0.223 1.08 0.025 1.06 (1.01-1.11) 0.022 C05 rs953861 158705160 G 28318/3047 0.161 0.172 1.08 0.052 1.07 (1.01-1.13) 0.022 C05 rs10045431 158747111 A 28238/3014 0.266 0.277 1.06 0.095 1.06 (1.01-1.11) 0.022 C14 rs8003722 68388015 A 28317/3046 0.106 0.116 1.11 0.024 1.07 (1.01-1.13) 0.024 C09 rs2297538 138684489 G 28226/3047 0.730 0.752 1.12 0.00079 1.06 (1.01-1.12) 0.027 C02 rs12329252 212093968 T 28321/3047 0.681 0.700 1.09 0.0059 1.04 (1.00-1.08) 0.029 C01 rs3748744 19828833 G 28280/3046 0.898 0.908 1.11 0.033 1.08 (1.01-1.16) 0.031 C05 rs4704400 76586766 T 28306/3046 0.498 0.514 1.07 0.023 1.04 (1.00-1.09) 0.036 C08 rs3102526 96858538 G 27995/3019 0.647 0.664 1.08 0.015 1.05 (1.00-1.09) 0.046 C15 rs2110209 24946433 A 28318/3047 0.048 0.057 1.19 0.0061 1.10 (1.00-1.20) 0.048 C16 rs1870843 81316815 T 28313/3047 0.602 0.621 1.08 0.0098 1.04 (1.00-1.09) 0.048 C08 rs3134517 96859237 G 28308/3047 0.647 0.664 1.08 0.018 1.05 (1.00-1.09) 0.049 C21 rs2828495 24038081 A 28316/3047 0.212 0.232 1.12 0.00089 1.05 (1.00-1.11) 0.051 C04 rs4282162 21426819 T 28305/3047 0.530 0.552 1.09 0.0031 1.04 (1.00-1.08) 0.052 C17 rs2955355 17889200 C 28312/3047 0.285 0.309 1.12 3.30E−04 1.04 (1.00-1.08) 0.052 C12 rs11045689 21092930 G 28210/3037 0.301 0.317 1.08 0.015 1.04 (1.00-1.08) 0.054 C05 rs7447732 158461713 C 28280/3045 0.320 0.337 1.08 0.015 1.04 (1.00-1.08) 0.064 C18 rs1365254 70238283 T 28319/3047 0.196 0.209 1.08 0.036 1.05 (1.00-1.11) 0.065 C13 rs1887263 22381716 A 28175/3042 0.204 0.217 1.08 0.037 1.05 (1.00-1.11) 0.066 C12 rs12304836 124654446 C 28205/3034 0.143 0.160 1.14 0.00095 1.05 (0.99-1.11) 0.084 C05 rs38055 52596401 T 28311/3047 0.387 0.399 1.05 0.091 1.03 (0.99-1.07) 0.091 C04 rs4697653 10337857 G 28161/3040 0.524 0.543 1.08 0.0081 1.03 (0.99-1.07) 0.1 C05 rs728676 118087433 T 28310/3046 0.444 0.468 1.10 0.001 1.03 (0.99-1.07) 0.1 C06 rs6905466 19958854 T 28315/3047 0.332 0.351 1.09 0.0058 1.04 (0.99-1.09) 0.1 C10 rs11199158 85297471 G 28319/3047 0.618 0.637 1.09 0.0062 1.03 (0.99-1.08) 0.1 C01 rs4845552 151746622 G 28269/3044 0.128 0.146 1.16 0.00041 1.05 (0.99-1.11) 0.11 C02 rs1395930 123468570 T 28303/3045 0.499 0.528 1.12 0.00012 1.03 (0.99-1.07) 0.12 C04 rs6534683 129601758 T 28310/3047 0.656 0.671 1.07 0.034 1.04 (0.99-1.08) 0.12 C02 rs6747236 35901725 T 28311/3047 0.717 0.734 1.09 0.0098 1.03 (0.99-1.08) 0.13 C06 rs3016536 162157939 G 28320/3047 0.519 0.537 1.08 0.013 1.03 (0.99-1.08) 0.13 C10 rs12269612 15475877 T 28314/3047 0.401 0.418 1.07 0.024 1.03 (0.99-1.07) 0.13 C17 rs854793 17971249 A 28313/3047 0.202 0.220 1.12 1.80E−03 1.03 (0.99-1.08) 0.14 C12 rs3742049 119438873 C 28300/3046 0.919 0.928 1.13 0.023 1.05 (0.98-1.13) 0.15 C01 rs2991515 57656898 T 28319/3047 0.483 0.508 1.10 0.00077 1.03 (0.99-1.07) 0.16 C18 rs4271662 26051291 C 28256/3039 0.587 0.599 1.05 0.092 1.03 (0.99-1.06) 0.16 C06 rs7739802 162154323 T 28266/3043 0.493 0.512 1.08 0.011 1.03 (0.99-1.07) 0.18 C08 rs10504537 73402234 A 28213/3035 0.881 0.891 1.11 0.027 1.04 (0.98-1.11) 0.2 C14 rs17776453 100774793 G 28313/3045 0.955 0.962 1.17 0.033 1.06 (0.97-1.16) 0.21 C10 rs7086224 30857283 A 28287/3045 0.419 0.434 1.06 0.04 1.03 (0.98-1.07) 0.22 C01 rs12724604 20948045 A 28248/3037 0.037 0.043 1.19 0.021 1.07 (0.96-1.19) 0.23 C03 rs9874646 62437858 T 28314/3046 0.717 0.726 1.05 0.16 1.02 (0.98-1.07) 0.24 C05 rs950195 97466690 G 28228/3046 0.633 0.654 1.10 0.002 1.02 (0.98-1.07) 0.25 C14 rs2281519 93846385 T 28281/3045 0.260 0.276 1.08 0.014 1.03 (0.98-1.08) 0.27 C10 rs4880711 5217871 C 27953/3015 0.351 0.359 1.04 0.26 1.02 (0.98-1.07) 0.34 C08 rs3931282 129179963 T 28319/3047 0.568 0.548 0.92 0.007 0.98 (0.94-1.02) 0.39 C10 rs11198993 85244450 A 28239/3038 0.697 0.717 1.10 0.0037 1.02 (0.97-1.06) 0.43 C12 rs1568383 88017285 T 28316/3045 0.098 0.110 1.14 0.0049 1.03 (0.96-1.09) 0.45 C06 rs9380681 37638433 C 28318/3047 0.311 0.319 1.04 0.25 1.02 (0.97-1.06) 0.46 C02 rs6709904 43933828 A 28315/3046 0.909 0.919 1.14 0.014 1.03 (0.96-1.10) 0.47 C10 rs2279434 45275070 T 28318/3047 0.067 0.076 1.15 0.014 1.03 (0.95-1.11) 0.49 C13 rs1375719 102208783 C 28316/3046 0.499 0.511 1.05 0.12 1.01 (0.97-1.06) 0.53 C10 rs7921473 85156395 G 28314/3047 0.820 0.838 1.13 0.0013 1.02 (0.96-1.07) 0.55 C14 rs1957860 53499105 T 28313/3047 0.448 0.444 0.98 0.55 1.01 (0.97-1.05) 0.55 C02 rs3943703 127613790 C 28280/3046 0.214 0.225 1.07 0.06 1.01 (0.96-1.07) 0.6 C08 rs7006687 18277862 T 28306/3044 0.579 0.604 1.11 0.00068 1.01 (0.97-1.05) 0.6 C12 rs1465026 65789635 G 28309/3047 0.837 0.849 1.10 0.024 1.01 (0.96-1.06) 0.67 C14 rs4444235 53480669 T 28305/3046 0.536 0.543 1.03 0.32 0.99 (0.96-1.03) 0.7 C02 rs921083 176453128 G 28310/3044 0.781 0.794 1.08 0.04 1.00 (0.96-1.05) 0.98 C08 rs4732849 28249765 T 28321/3047 0.275 0.285 1.05 0.13 1.00 (0.96-1.04) 0.99

TABLE 5 Surrogate markers for marker rs11751605. The markers were selected from the Caucasian data set of the HapMap sample (CEU; see http://www.hapmap.org), using a cutoff of r² of 0.2. The search was done in a 2Mb interval flanking the rs11751605 marker. The table shows (1) chromosome; (2) SNP rs name; (3) position in NCBI build 36; (4) value for D′ to rs11751605; (5) value for r² to rs11751605; (6) P-value of the association with rs11751605. Surrogates of rs11751605 based on HapMap CEU v22 Pos in Chr SNP Build 36 D′ R2 P C06 rs3798156 160596206 0.55 0.22 5.8E−05 C06 rs3127573 160601383 0.80 0.43 4.9E−08 C06 rs3127572 160602208 0.71 0.36 4.7E−07 C06 rs3119309 160605062 0.80 0.44 2.4E−08 C06 rs7756836 160609247 0.80 0.44 2.4E−08 C06 rs7757336 160609548 0.56 0.29 3.6E−06 C06 rs3119310 160612365 0.80 0.44 2.4E−08 C06 rs3119311 160613097 0.80 0.44 2.4E−08 C06 rs3127578 160618145 0.80 0.44 2.4E−08 C06 rs3127586 160624902 0.85 0.67 9.9E−13 C06 rs12206585 160633514 0.92 0.72 1.1E−13 C06 rs12203303 160633686 0.83 0.55 4.6E−09 C06 rs2183470 160635083 0.85 0.68 1.5E−13 C06 rs3120151 160637462 0.85 0.68 1.5E−13 C06 rs3103350 160642995 0.85 0.68 1.5E−13 C06 rs3127583 160647121 0.85 0.68 1.5E−13 C06 rs3106172 160647965 0.85 0.64 1.2E−10 C06 rs3106170 160649914 0.86 0.72 6.6E−13 C06 rs3125057 160651662 0.84 0.60 2.7E−11 C06 rs3125056 160655271 0.87 0.45 4.8E−06 C06 rs3125055 160656777 0.86 0.37 2.2E−06 C06 rs3106167 160657380 0.85 0.68 1.5E−13 C06 rs3127591 160657792 0.92 0.71 3.2E−12 C06 rs3125052 160658363 0.85 0.68 1.5E−13 C06 rs3120140 160658821 0.90 0.58 1.1E−08 C06 rs3103349 160660711 0.85 0.68 1.5E−13 C06 rs3125050 160660826 0.85 0.68 1.5E−13 C06 rs3120139 160661612 0.85 0.68 1.5E−13 C06 rs3125049 160674702 0.86 0.74 4.0E−15 C06 rs12209517 160676726 0.72 0.46 2.4E−07 C06 rs3120137 160691182 0.93 0.87 1.2E−17 C06 rs3127574 160711360 1.00 0.20 3.1E−08 C06 rs6905958 160717615 1.00 0.20 3.1E−08 C06 rs3123633 160719595 1.00 0.20 3.1E−08 C06 rs3123634 160722229 1.00 0.20 3.1E−08 C06 rs1317652 160727151 1.00 0.20 2.9E−08 C06 rs884742 160727422 1.00 0.20 3.1E−08 C06 rs7740824 160728891 0.91 0.45 1.1E−09 C06 rs3105748 160730710 1.00 0.20 3.1E−08 C06 rs3105749 160740968 1.00 0.20 3.1E−08 C06 rs3105752 160742915 1.00 0.20 2.9E−08 C06 rs10945670 160747660 1.00 0.20 3.1E−08 C06 rs10806731 160747825 1.00 0.20 3.1E−08 C06 rs9364554 160753654 0.92 0.46 5.2E−11 C06 rs12194182 160754505 0.92 0.46 5.2E−11 C06 rs3106166 160758351 1.00 0.22 2.2E−08 C06 rs10455782 160759340 1.00 0.39 4.6E−12 C06 rs7758229 160760242 1.00 0.38 2.2E−11 C06 rs3123636 160762527 1.00 0.37 1.9E−11 C06 rs3106164 160770263 1.00 0.37 6.9E−10 C06 rs388170 160773276 1.00 0.36 1.0E−11 C06 rs9365164 160776833 0.91 0.33 3.9E−08 C06 rs2292334 160778178 1.00 0.33 2.8E−10 C06 rs2048327 160783522 1.00 0.33 4.5E−11 C06 rs7769879 160785635 1.00 0.33 4.5E−11 C06 rs3918285 160788644 1.00 0.33 4.5E−11 C06 rs3918286 160788658 1.00 0.33 1.1E−10 C06 rs1810126 160792141 1.00 0.34 3.0E−11 C06 rs3088442 160792642 1.00 0.33 4.5E−11 C06 rs2063347 160802019 1.00 0.33 4.5E−11 C06 rs3106162 160803284 1.00 0.33 4.5E−11 C06 rs2063346 160804265 1.00 0.34 3.5E−11 C06 rs1112073 160810832 1.00 0.38 8.0E−12 C06 rs3127602 160812231 1.00 0.37 8.9E−12 C06 rs3123629 160826076 1.00 0.37 7.6E−12 C06 rs3127599 160827124 1.00 0.37 7.6E−12 C06 rs3127569 160837549 1.00 0.39 4.0E−12 C06 rs3127596 160873025 1.00 0.38 4.7E−12 C06 rs3124785 160874495 1.00 0.38 7.6E−12 C06 rs11751605 160883220 1.00 1.00 0.0E+00 C06 rs10455872 160930108 1.00 0.55 1.3E−11 C06 rs2315065 161028134 0.66 0.35 4.6E−07 C06 rs9458266 161798149 0.58 0.22 1.7E−04

TABLE 6 Key to the sequence listing provided herein. Seq ID No: SNP 1 rs11751605 2 rs6076623 3 rs1412444 4 rs2163612 5 rs1029396 6 rs2243547 7 rs12534186 8 rs12134779 9 rs7158073 10 rs254850 11 rs2417821 12 rs7661204 13 rs4921437 14 rs832540 15 rs324594 16 rs1741318 17 rs9902941 18 rs7709212 19 rs2946534 20 rs6556861 21 rs8050136 22 rs3751812 23 rs4769613 24 rs2243548 25 rs12459084 26 rs2074464 27 rs2244871 28 rs270654 29 rs854787 30 rs7944761 31 rs4779984 32 rs6502622 33 rs3183702 34 rs1433048 35 rs4925119 36 rs2476601 37 rs870347 38 rs334198 39 rs854813 40 rs7753765 41 rs4925114 42 rs270661 43 rs953861 44 rs10045431 45 rs8003722 46 rs2297538 47 rs12329252 48 rs3748744 49 rs4704400 50 rs3102526 51 rs2110209 52 rs1870843 53 rs3134517 54 rs2828495 55 rs4282162 56 rs2955355 57 rs11045689 58 rs7447732 59 rs1365254 60 rs1887263 61 rs12304836 62 rs38055 63 rs4697653 64 rs728676 65 rs6905466 66 rs11199158 67 rs4845552 68 rs1395930 69 rs6534683 70 rs6747236 71 rs3016536 72 rs12269612 73 rs854793 74 rs3742049 75 rs2991515 76 rs4271662 77 rs7739802 78 rs10504537 79 rs17776453 80 rs7086224 81 rs12724604 82 rs9874646 83 rs950195 84 rs2281519 85 rs4880711 86 rs3931282 87 rs11198993 88 rs1568383 89 rs9380681 90 rs6709904 91 rs2279434 92 rs1375719 93 rs7921473 94 rs1957860 95 rs3943703 96 rs7006687 97 rs1465026 98 rs4444235 99 rs921083 100 rs4732849 101 rs3798156 102 rs3127573 103 rs3127572 104 rs3119309 105 rs7756836 106 rs7757336 107 rs3119310 108 rs3119311 109 rs3127578 110 rs3127586 111 rs12206585 112 rs12203303 113 rs2183470 114 rs3120151 115 rs3103350 116 rs3127583 117 rs3106172 118 rs3106170 119 rs3125057 120 rs3125056 121 rs3125055 122 rs3106167 123 rs3127591 124 rs3125052 125 rs3120140 126 rs3103349 127 rs3125050 128 rs3120139 129 rs3125049 130 rs12209517 131 rs3120137 132 rs3127574 133 rs6905958 134 rs3123633 135 rs3123634 136 rs1317652 137 rs884742 138 rs7740824 139 rs3105748 140 rs3105749 141 rs3105752 142 rs10945670 143 rs10806731 144 rs9364554 145 rs12194182 146 rs3106166 147 rs10455782 148 rs7758229 149 rs3123636 150 rs3106164 151 rs388170 152 rs9365164 153 rs2292334 154 rs2048327 155 rs7769879 156 rs3918285 157 rs3918286 158 rs1810126 159 rs3088442 160 rs2063347 161 rs3106162 162 rs2063346 163 rs1112073 164 rs3127602 165 rs3123629 166 rs3127599 167 rs3127569 168 rs3127596 169 rs3124785 170 rs10455872 171 rs2315065 172 rs9458266 

1. A method for determining a susceptibility to myocardial infarction or coronary artery disease in a human individual, comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual or in a genotype dataset derived from the individual, wherein the at least one polymorphic marker is selected from the markers set forth in Table 4, and markers in linkage disequilibrium therewith, and wherein the presence of the at least one allele is indicative of a susceptibility to cardiovascular disease.
 2. The method according to claim 1, wherein the at least one polymorphic marker is selected from rs11751605 (SEQ ID NO:1), rs6076623 (SEQ ID NO:2), rs1412444 (SEQ ID NO:3), rs2163612 (SEQ ID NO:4), rs1029396 (SEQ ID NO:5), rs2243547 (SEQ ID NO:6), rs12534186 (SEQ ID NO:7), rs12134779 (SEQ ID NO:8), rs7158073 (SEQ ID NO:9), rs254850 (SEQ ID NO:10), rs2417821 (SEQ ID NO:11), rs7661204 (SEQ ID NO:12), rs4921437 (SEQ ID NO:13), rs832540 (SEQ ID NO:14), rs324594 (SEQ ID NO:15), rs1741318 (SEQ ID NO:16), rs9902941 (SEQ ID NO:17), rs7709212 (SEQ ID NO:18), rs2946534 (SEQ ID NO:19), rs6556861 (SEQ ID NO:20), rs8050136 (SEQ ID NO:21), rs3751812 (SEQ ID NO:22), rs4769613 (SEQ ID NO:23), rs2243548 (SEQ ID NO:24), rs12459084 (SEQ ID NO:25), rs2074464 (SEQ ID NO:26), rs2244871 (SEQ ID NO:27), rs270654 (SEQ ID NO:28), rs854787 (SEQ ID NO:29), rs7944761 (SEQ ID NO:30), rs4779984 (SEQ ID NO:31), rs6502622 (SEQ ID NO:32), rs3183702 (SEQ ID NO:33), rs1433048 (SEQ ID NO:34), rs4925119 (SEQ ID NO:35), rs2476601 (SEQ ID NO:36), rs870347 (SEQ ID NO:37), rs334198 (SEQ ID NO:38), rs854813 (SEQ ID NO:39), rs7753765 (SEQ ID NO:40), rs4925114 (SEQ ID NO:41), rs270661 (SEQ ID NO:42), rs953861 (SEQ ID NO:43), rs10045431 (SEQ ID NO:44), rs8003722 (SEQ ID NO:45), rs2297538 (SEQ ID NO:46), rs12329252 (SEQ ID NO:47), rs3748744 (SEQ ID NO:48), rs4704400 (SEQ ID NO:49), rs3102526 (SEQ ID NO:50), rs2110209 (SEQ ID NO:51), rs1870843 (SEQ ID NO:52) and rs3134517 (SEQ ID NO:53), and markers in linkage disequilibrium therewith.
 3. The method according to claim 2, wherein the at least one polymorphic marker is selected from rs11751605 (SEQ ID NO:1), rs6076623 (SEQ ID NO:2), rs1412444 (SEQ ID NO:3), rs2163612 (SEQ ID NO:4), rs1029396 (SEQ ID NO:5), rs2243547 (SEQ ID NO:6), rs12534186 (SEQ ID NO:7), rs12134779 (SEQ ID NO:8) and rs7158073 (SEQ ID NO:9), and markers in linkage disequilibrium therewith.
 4. The method according to any of the preceding claims, wherein the at least one polymorphic marker is selected from rs11751605 (SEQ ID NO:1), rs6076623 (SEQ ID NO:2), rs1412444 (SEQ ID NO:3), rs2163612 (SEQ ID NO:4) and rs1029396 (SEQ ID NO:5), and markers in linkage disequilibrium therewith.
 5. The method according to any of the preceding claims, wherein the at least one polymorphic marker is selected from rs11751605 (SEQ ID NO:1), and markers in linkage disequilibrium therewith.
 6. The method according to any of the preceding claims, further comprising assessing the frequency of at least one haplotype in the individual.
 7. The method of any of the preceding claims, wherein the susceptibility conferred by the presence of the at least one allele or haplotype is increased susceptibility.
 8. The method according to claim 7, wherein the presence of allele C in rs11751605, is indicative of increased susceptibility to myocardial infarction or coronary artery disease.
 9. The method according to claim 7 or 8, wherein the presence of the at least one allele or haplotype is indicative of increased susceptibility with a relative risk (RR) or odds ratio (OR) of at least 1.15.
 10. The method according to any of the claims 1-6, wherein the susceptibility conferred by the presence of the at least one allele or haplotype is decreased susceptibility.
 11. A method of identification of a marker for use in assessing susceptibility to coronary artery disease or myocardial infarction, the method comprising a. identifying at least one polymorphic marker in linkage disequilibrium with at least one of the markers set forth in Table 4; b. determining the genotype status of a sample of individuals diagnosed with, or having a susceptibility to, coronary artery disease or myocardial infarction; and c. determining the genotype status of a sample of control individuals; wherein a significant difference in frequency of at least one allele in at least one polymorphism in individuals diagnosed with, or having a susceptibility to, coronary artery disease or myocardial infarction, as compared with the frequency of the at least one allele in the control sample is indicative of the at least one polymorphism being useful for assessing susceptibility to coronary artery disease or myocardial infarction.
 12. The method according to claim 11, wherein an increase in frequency of the at least one allele in the at least one polymorphism in individuals diagnosed with, or having a susceptibility to, coronary artery disease or myocardial infarction, as compared with the frequency of the at least one allele in the control sample is indicative of the at least one polymorphism being useful for assessing increased susceptibility to coronary artery disease or myocardial infarction.
 13. The method according to claim 11 or claim 12, wherein a decrease in frequency of the at least one allele in the at least one polymorphism in individuals diagnosed with, or having a susceptibility to, coronary artery disease or myocardial infarction, as compared with the frequency of the at least one allele in the control sample is indicative of the at least one polymorphism being useful for assessing decreased susceptibility to, or protection against, coronary artery disease or myocardial infarction.
 14. The method according to any of the preceding claims wherein the presence of the marker or haplotype is indicative of a different response rate of the subject to a particular treatment modality for myocardial infarction or coronary artery disease.
 15. The method according to claim 14, wherein the treatment modality is a coronary stenosis method selected from balloon angioplasty, stenting, cutting balloon angioplasty, percutaneous transluminal coronary angioplasty (PTCA), directional coronary atherectomy, rotational coronary atherectomy, brachytherapy, drug-eluting stent (DES) insertion, metal stent insertion, and coronary artery surgery.
 16. The method of claim 14, wherein the treatment modality is administration of a therapeutic agent for preventing and/or ameliorating symptoms associated with the Cardiovascular disease.
 17. A method of assessing an individual for probability of response to a therapeutic agent for preventing and/or ameliorating symptoms associated with coronary artery disease or myocardial infarction, comprising: determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual, wherein the at least one polymorphic marker is selected from the group consisting of the polymorphic markers set forth in Table 4, and markers in linkage disequilibrium therewith, wherein the presence of the at least one allele of the at least one marker is indicative of a probability of a positive response to the therapeutic agent.
 18. A method of predicting prognosis of an individual diagnosed with coronary artery disease or myocardial infarction, the method comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual, wherein the at least one polymorphic marker is selected from the group consisting of the polymorphic markers set forth in Table 4, and markers in linkage disequilibrium therewith, wherein the presence of the at least one allele is indicative of a worse prognosis of the coronary artery disease or myocardial infarction in the individual.
 19. A method of monitoring progress of treatment of an individual undergoing treatment for coronary artery disease or myocardial infarction, the method comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual, wherein the at least one polymorphic marker is selected from the markers set forth in Tables 4, and markers in linkage disequilibrium therewith, wherein the presence of the at least one allele is indicative of the treatment outcome of the individual.
 20. The method according to any of the claims 11-19, wherein the at least one marker is selected from rs11751605 (SEQ ID NO:1), rs6076623 (SEQ ID NO:2), rs1412444 (SEQ ID NO:3), rs2163612 (SEQ ID NO:4), rs1029396 (SEQ ID NO:5), rs2243547 (SEQ ID NO:6), rs12534186 (SEQ ID NO:7), rs12134779 (SEQ ID NO:8) and rs7158073 (SEQ ID NO:9), and markers in linkage disequilibrium therewith.
 21. The method according to claim 20, wherein the at least one marker is rs11751605.
 22. The method of any of the preceding claims, further comprising assessing at least one biomarker in a sample from the individual.
 23. The method of claim 22, wherein the biomarker is a cardiac marker or an inflammatory marker.
 24. The method of claim 22 or claim 23, wherein the at least one biomarker is selected from creatin kinase, troponin, glycogen phosphorylase, C-reactive protein (CRP), serum amyloid A, fibrinogen, interleukin-6, tissue necrosis factor-alpha, soluble vascular cell adhesion molecules (sVCAM), soluble intervascular adhesion molecules (sICAM), E-selectin, matrix metalloprotease type-1, matrix metalloprotease type-2, matrix metalloprotease type-3, matrix metalloprotease type-9, serum sCD40L, leukotrienes, leukotriene metabolites, interleukin-6, tissue necrosis factor-alpha, myeloperoxidase (MPO), and N-tyrosine.
 25. The method of claim 24, wherein the leukotriene is selected from LTB4, LTC4, LTD4 and LTE4.
 26. The method of any of the preceding claims, further comprising analyzing a sample comprising genomic DNA from the human individual or a genotype dataset derived from the human individual for the presence or absence of at least one at-risk allele of at least one at-risk variant for coronary artery disease or myocardial infarction not in linkage disequilibrium with any one of the markers set forth in Table
 4. 27. The method of any of the claims 1-6, comprising determining the presence or absence of at least one allele in at least two polymorphic markers, wherein the presence of the at least one allele in the at least two polymorphic markers is indicative of an increased susceptibility to coronary artery disease or myocardial infarction.
 28. The method of any of the preceding claims, further comprising analyzing non-genetic information to make risk assessment, diagnosis, or prognosis of the individual.
 29. The method of claim 28, wherein the non-genetic information is selected from age, gender, ethnicity, socioeconomic status, previous disease diagnosis, medical history of subject, family history of coronary artery disease or myocardial infarction, biochemical measurements, and clinical measurements.
 30. A kit for assessing susceptibility to coronary artery disease or myocardial infarction in a human individual, the kit comprising reagents for selectively detecting at least one allele of at least one polymorphic marker in the genome of the individual, wherein the polymorphic marker is selected from the markers set forth in Tables 4, and markers in linkage disequilibrium therewith, and wherein the presence of the at least one allele is indicative of a susceptibility to coronary artery disease or myocardial infarction.
 31. The kit of claim 30, wherein the at least one polymorphic marker is selected from rs11751605 (SEQ ID NO:1), rs6076623 (SEQ ID NO:2), rs1412444 (SEQ ID NO:3), rs2163612 (SEQ ID NO:4), rs1029396 (SEQ ID NO:5), rs2243547 (SEQ ID NO:6), rs12534186 (SEQ ID NO:7), rs12134779 (SEQ ID NO:8) and rs7158073 (SEQ ID NO:9), and markers in linkage disequilibrium therewith.
 32. The method kit according to claim 30 or claim 31, wherein the at least one polymorphic marker is rs11751605 (SEQ ID NO:1).
 33. The kit according to any of the claims 30-32, wherein the reagents comprise at least one contiguous oligonucleotide that hybridizes to a fragment of the genome of the individual comprising the at least one polymorphic marker, a buffer and a detectable label.
 34. The kit according to any of the claims 30-32, wherein the reagents comprise at least one pair of oligonucleotides that hybridize to opposite strands of a genomic nucleic acid segment obtained from the subject, wherein each oligonucleotide primer pair is designed to selectively amplify a fragment of the genome of the individual that includes one polymorphic marker, and wherein the fragment is at least 30 base pairs in size.
 35. The kit according to claim 33 or 34, wherein the at least one oligonucleotide is completely complementary to the genome of the individual.
 36. The kit according to any of the claims 33-35, wherein the oligonucleotide is about 18 to about 50 nucleotides in length.
 37. The kit according any of the claims 33-36, wherein the oligonucleotide is 20-30 nucleotides in length.
 38. The kit according to any of the claims 30-37, wherein the kit comprises: a. a detection oligonucleotide probe that is from 5-100 nucleotides in length; b. an enhancer oligonucleotide probe that is from 5-100 nucleotides in length; and c. an endonuclease enzyme; wherein the detection oligonucleotide probe specifically hybridizes to a first segment of the nucleic acid whose nucleotide sequence is set forth in any one of SEQ ID NO:1-172 and wherein the detection oligonucleotide probe comprises a detectable label at its 3′ terminus and a quenching moiety at its 5′ terminus; wherein the enhancer oligonucleotide is from 5-100 nucleotides in length and is complementary to a second segment of the nucleotide sequence that is 5′ relative to the oligonucleotide probe, such that the enhancer oligonucleotide is located 3′ relative to the detection oligonucleotide probe when both oligonucleotides are hybridized to the nucleic acid; wherein a single base gap exists between the first segment and the second segment, such that when the oligonucleotide probe and the enhancer oligonucleotide probe are both hybridized to the nucleic acid, a single base gap exists between the oligonucleotides; and wherein treating the nucleic acid with the endonuclease will cleave the detectable label from the 3′ terminus of the detection probe to release free detectable label when the detection probe is hybridized to the nucleic acid.
 39. Use of an oligonucleotide probe in the manufacture of a reagent for diagnosing and/or assessing susceptibility to coronary artery disease or myocardial infarction in a human individual, wherein the probe hybridizes to a segment of a nucleic acid whose nucleotide sequence is set forth in any one of SEQ ID NO:1-172, wherein the probe is 15-500 nucleotides in length.
 40. A computer-readable medium on which is stored: a. an identifier for at least one polymorphic marker; b. an indicator of the frequency of at least one allele of said at least one polymorphic marker in a plurality of individuals diagnosed with coronary artery disease or myocardial infarction; and c. an indicator of the frequency of the least one allele of said at least one polymorphic markers in a plurality of reference individuals; wherein the at least one polymorphic marker is selected from the polymorphic markers set forth in Table 4, and polymorphic markers in linkage disequilibrium therewith.
 41. The medium according to claim 40, wherein the polymorphic marker is selected from rs11751605 (SEQ ID NO:1), rs6076623 (SEQ ID NO:2), rs1412444 (SEQ ID NO:3), rs2163612 (SEQ ID NO:4), rs1029396 (SEQ ID NO:5), rs2243547 (SEQ ID NO:6), rs12534186 (SEQ ID NO:7), rs12134779 (SEQ ID NO:8) and rs7158073 (SEQ ID NO:9), and markers in linkage disequilibrium therewith.
 42. An apparatus for determining a genetic indicator for coronary artery disease or myocardial infarction in a human individual, comprising: a computer readable memory; and a routine stored on the computer readable memory; wherein the routine is adapted to be executed on a processor to analyze marker and/or haplotype information for at least one human individual with respect to at least one polymorphic marker selected from the markers set forth in Table 4, and markers in linkage disequilibrium therewith, and generate an output based on the marker or haplotype information, wherein the output comprises a risk measure of the at least one marker or haplotype as a genetic indicator of coronary artery disease or myocardial infarction for the human individual.
 43. The apparatus of claim 42, wherein the routine further comprises an indicator of the frequency of at least one allele of at least one polymorphic marker or at least one haplotype in a plurality of individuals diagnosed with coronary artery disease or myocardial infarction, and an indicator of the frequency of at the least one allele of at least one polymorphic marker or at least one haplotype in a plurality of reference individuals, and wherein a risk measure is based on a comparison of the at least one marker and/or haplotype status for the human individual to the indicator of the frequency of the at least one marker and/or haplotype information for the plurality of individuals diagnosed with coronary artery disease or myocardial infarction.
 44. The apparatus according to claim 42 or 43, wherein the at least one polymorphic marker is selected from rs11751605 (SEQ ID NO:1), rs6076623 (SEQ ID NO:2), rs1412444 (SEQ ID NO:3), rs2163612 (SEQ ID NO:4), rs1029396 (SEQ ID NO:5), rs2243547 (SEQ ID NO:6), rs12534186 (SEQ ID NO:7), rs12134779 (SEQ ID NO:8) and rs7158073 (SEQ ID NO:9), and markers in linkage disequilibrium therewith.
 45. The apparatus or medium according to any of the claims 42-44, wherein the at least one polymorphic marker is rs11751605 (SEQ ID NO:1).
 46. The apparatus of any of the claims 42-45, wherein the risk measure is characterized by an Odds Ratio (OR) or a Relative Risk (RR).
 47. The method, use, medium or apparatus according to any of the preceding claims, wherein linkage disequilibrium between markers is characterized by particular numerical values for the linkage disequilibrium measures r² and/or |D′|.
 48. The method according to claim 47, wherein linkage disequilibrium is characterized by a numerical values for r² of greater than 0.2.
 49. The method according to claim 47 or claim 48, wherein linkage disequilibrium is characterized by numerical values for r² of greater than 0.5.
 50. The method according to claim 47, wherein linkage disequilibrium is characterized by numerical values for r² of greater than 0.2 and/or |D′| of greater than 0.8 